Actionability Working Group Evidence-based Summaries

The summaries provide information on gene-condition pairs that meet a clinical actionability threshold for pathologic variants in the gene, and are prepared using a transparent, systematic, evidence-based process. A protocol guides the summary development, which includes quality rating of the evidence. An expert panel reviews the summaries and applies a semi-quantitative method to score the overall clinical actionability of gene variants discovered incidental to another diagnostic investigation. For scoring, specific intervention-outcome pairs are chosen for each genetic disorder under consideration. Clinical interventions are chosen based on their effectiveness for prevention or delay of clinical disease, lowered clinical burden, or improved clinical outcomes in a previously undiagnosed adult.


Semi-quantitative Metric (SQM)

Category

Levels

Level of Evidence

Severity

3 - sudden death

2 - possible death or major morbidity

1 -  modest morbidity

0 - minimal or no morbidity

NA

Likelihood of Disease

3 - >40% chance

2 - 5-39% chance

1 - 1-4% chance

0 - <1% chance or unknown

A = substantial evidence

B = moderate evidence

C = minimal evidence

D = poor evidence

E = expert contributed evidence

Efficacy of Intervention

3 - highly effective
2 - moderately effective
1 - minimally effective

0 - ineffective/no intervention

IN* – ineffective/no intervention

A = substantial evidence

B = moderate evidence

C = minimal evidence

D = poor or conflicting evidence

E = expert contributed evidence

Nature of Intervention

3 - low risk/medically acceptable/ low intensity intervention

2 - moderately acceptable/risk/ intensive interventions

1 - greater risk/less acceptable/ substantial interventions

0 - high risk/poor acceptable/ intensive or no intervention

NA

Semi-quantitative Metric (SQM) Scoring Methology
Disorder curated HGNC Gene Symbol(s) Outcome/ Intervention Pair Severity Likelihood Effectiveness Nature of the Intervention Total
Acute Intermittent Porphyria
OMIM: 176000
Report
HMBS Neurovisceral attacks/Optimal clinical management to reduce risk of attacks (e.g., avoidance of harmful medications, dietary advice, treatment of infections, avoidance of smoking/alcohol) 2 2C 2B 3 9CB
Hepatocellular carcinoma/Liver US surveillance 2 2C 3C* 3 10CC
Morbidity of acute attacks/Optimal treatment (Hemin) in the event of an attack 2 2C 3B 3 10CB
Adrenoleukodystrophy
OMIM: 300371
Report
ABCD1 Neurological/Cognitive decline / Neurological surveillance to plan initiation of HCT 2 3C 3C 3 11CC
Adrenal insufficiency (males only) / Monitoring adrenal hormones with replacement as needed 1 2C 3C 3 9CC
Adult‑onset type II citrullinemia
OMIM: 603471
Report
SLC25A13 Hepatic encephalopathy/Dietary modification with arginine and sodium pyruvate supplementation 2 0D 1E 3 6DE
Liver failure/Liver transplantation 2 0D 3C 0 5D
Alpha-1 Antitrypsin Deficiency
OMIM: 613490
Report
SERPINA1 Identify those at risk to and institute interventions appropriate to severity/Serum A1AT measurement 2 3C 3C 3 11CC
COPD/Smoking cessation 2 3C 3A 3 11CA
Liver disease/Limit alcohol consumption 2 2C 2C 3 9CC
Emphysema/A1AT augmentation therapy 2 3C 0D 2 7CD
Arrhythmogenic Right Ventricular Dysplasia,Familial, 9; ARVD9
OMIM: 609040
Report
PKP2 Sudden cardiac death/Implantable Cardioverter Defibrillator 3 2C 2A 2 9CA
Sudden cardiac death/Antiarrhythmic therapy 3 2C 1C 2 8CC
Arrhythmogenic Right Ventricular Dysplasia, Familial, 8; ARVD8
OMIM: 607450
Report
DSP Sudden cardiac death/Implantable Cardioverter Defibrillator 3 2C 2A 2 9CA
Sudden cardiac death/Antiarrhythmic therapy 3 2C 1C 2 8CC
Arrhythmogenic Right Ventricular Dysplasia,Familial, 11; ARVD11
OMIM: 610476
Report
DSC2 Sudden cardiac death/Implantable Cardioverter Defibrillator 3 2C 2A 2 9CA
Sudden cardiac death/Antiarrhythmic therapy 3 2C 1C 2 8CC
Arrhythmogenic Right Ventricular Dysplasia, Familial, 5; ARVD5
OMIM: 604400
Report
TMEM43 Sudden cardiac death/Implantable Cardioverter Defibrillator 3 2C 2A 2 9CA
Sudden cardiac death/Antiarrhythmic therapy 3 2C 1C 2 8CC
Arrhythmogenic Right Ventricular Dysplasia, Familial, 10; ARVD10
OMIM: 610193
Report
DSG2 Sudden cardiac death/Implantable Cardioverter Defibrillator 3 2C 2A 2 9CA
Sudden cardiac death/Antiarrhythmic therapy 3 2C 1C 2 8CC
Polycystic Kidney Disease 1; PKD1
OMIM: 173900
Report
PKD1 End Stage Renal Disease/Blood Pressure Control 2 3C 1B 3 9CB
Significant Morbidity/MRA Surveillance 2 2C 1C 3 8CC
Aortic Valve Replacement/Aortic Surveillance 2 0D 3E 3 8DE
Polycystic Kidney Disease 2; PKD2
OMIM: 613095
Report
PKD2 End Stage Renal Disease/Blood Pressure Control 2 3C 1B 3 9CB
Significant Morbidity/MRA Surveillance 2 2C 1C 3 8CC
Aortic Valve Replacement/Aortic Surveillance 2 0D 3E 3 8DE
Basal Cell Nevus Syndrome (BCNS)
OMIM: 109400
Report
PTCH1 Morbidity from odontogenic keratocysts/Panorex surveillance 1 3C 0D 3 7CD
Morbidity from basal cell carcinomas/Skin surveillance 2 3C 2E 3 10CE
Morbidity from basal cell carcinomas/Sun avoidance 2 3C 2C 3 10CC
Morbidity from basal cell carcinomas/Minimization of radiation 2 3C 2C 2 9CC
Biotinidase Deficiency
OMIM: 253260
Report
BTD Neurological complications/Biotin therapy 2 3C 3C 3 11CC
Cutaneous manifestations/Biotin therapy 1 3C 3C 3 10CC
Birt-Hogg-Dubé Syndrome
OMIM: 135150
Report
FLCN Morbidity and mortality from masses/Imaging to detect renal masses when intervention is effective 2 2E 2C 3 9EC
Brugada Syndrome
OMIM: 601144
Report
SCN5A Sudden Cardiac Death/Implantable Cardioverter Defibrillator 3 2C 2B 2 9CB
CADASIL (Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukocenphalopathy, type 1)
OMIM: 125310
Report
NOTCH3 Stroke/specialist care and management (initial evaluations, antiplatelet therapy, balanced diet, monitoring during anesthesia, cholinesterase inhibitor, and psychological counseling) 2 3C 1A 3 9CA
Catecholaminergic polymorphic ventricular tachycardia
OMIM: 604772
Report
RYR2 Sudden Cardiac Death/Beta Blockers 3 2E 2B 3 10EB
Cerebral cavernous malformations 1
OMIM: 116860
Report
KRIT1 Hemorrhage/Medication (simvastatin, fasudil) 2 2C 0D 3 7CD
Hemorrhage/MRI 2 2C 0C 3 7CC
Hemorrhage/Delivery management 2 2C 1C 3 8CC
Cerebral cavernous malformations 2
OMIM: 603284
Report
CCM2 Hemorrhage/Medication (simvastatin, fasudil) 2 2C 0D 3 7CD
Hemorrhage/MRI 2 2C 0C 3 7CC
Hemorrhage/Delivery management 2 2C 1C 3 8CC
Cerebral cavernous malformations 3
OMIM: 603285
Report
PDCD10 Hemorrhage/Medication (simvastatin, fasudil) 2 2C 0D 3 7CD
Hemorrhage/MRI 2 2C 0C 3 7CC
Hemorrhage/Delivery management 2 2C 1C 3 8CC
Charcot-Marie-Tooth Disease Type I
OMIM: 118220
Report
PMP22 Demyelinating Peripheral Neuropathy/Avoidance of Vincristine 1 3C 3C 3 10CC
Demyelinating Peripheral Neuropathy/Regular Medical Evaluations 1 3C 0C 3 7CC
Charcot-Marie-Tooth Disease Type 1B
OMIM: 118200
Report
MPZ Demyelinating peripheral neuropathy/Regular medical evaluations 1 3C 0C 3 7CC
Demyelinating peripheral neuropathy/Avoidance of Vincristine 1 3C 3C 3 10CC
Charcot-Marie-Tooth Disease Type 1C
OMIM: 601098
Report
LITAF Demyelinating peripheral neuropathy/Regular medical evaluations 1 3C 0C 3 7CC
Demyelinating peripheral neuropathy/Avoidance of Vincristine 1 3C 3C 3 10CC
Charcot-Marie-Tooth Disease Type 1D
OMIM: 607678
Report
EGR2 Demyelinating peripheral neuropathy/Regular medical evaluations 1 3C 0C 3 7CC
Demyelinating peripheral neuropathy/Avoidance of Vincristine 1 3C 3C 3 10CC
Charcot-Marie-Tooth Disease Type 1F
OMIM: 607734
Report
NEFL Demyelinating peripheral neuropathy/Regular medical evaluations 1 3C 0C 3 7CC
Demyelinating peripheral neuropathy/Avoidance of Vincristine 1 3C 3C 3 10CC
Deficiency of very long-chain acyl-coA dehydrogenase (ACADVLD)
OMIM: 201475
Report
ACADVL Rhabdomyolosis, muscle cramps, and exercise intolerance/Multidisciplinary care (which includes initial evaluation with echocardiography, dietary modification with MCT supplementation as appropriate, and exercise guidance) 2 2D 2D 3 9DD
Perinatal or delivery complications/High risk pregnancy management 2 0D 2D 3 7DD
Surgical complications/High risk surgical and anesthesia management 2 0D 2D 3 7DD
Dilated Cardiomyopathy 1A
OMIM: 115200
Report
LMNA Heart failure/Surveillance and ACE inhibitors 2 3C 2B 3 10CB
Sudden cardiac death/Surveillance and Pharmacotherapy 3 3C 2C 3 11CC
Sudden cardiac death/Surveillance and ICD 3 3C 2B 2 10CB
Dilated Cardiomyopathy 1D
OMIM: 601494
Report
TNNT2 Heart failure/Surveillance and ACE inhibitors 2 3C 2B 3 10CB
Sudden cardiac death/Surveillance and Pharmacotherapy 3 3C 2C 3 11CC
Sudden cardiac death/Surveillance and ICD 3 3C 2B 2 10CB
Dopa-responsive dystonia, autosomal dominant
OMIM: 128230
Report
GCH1 Neuromuscular dysfunction / Regular examinations and surveillance by a movement disorder specialist 2 3C 0D 3 8CD
Neuromuscular dysfunction / Levodopa therapy 2 3C 3C 3 11CC
Neuromuscular dysfunction / Avoidance of oral contraceptives 2 3C 2C 2 9CC
Ehlers-Danlos Syndrome, Classic Type
OMIM: 130000
Report
COL5A1 Musculoskeletal morbidity/Physical/occupational therapy program 1 3E 1D 3 8ED
Perinatal complications/High-risk pregnancy management 2 0D 0C 3 5DC
Ehlers-Danlos Syndrome, Classic Type
OMIM: 130000
Report
COL5A2 Musculoskeletal morbidity/Physical/occupational therapy program 1 3E 1D 3 8ED
Perinatal complications/High-risk pregnancy management 2 0D 0C 3 5DC
Ehlers-Danlos Syndrome Type IV
OMIM: 130050
Report
COL3A1 Vascular or organ rupture or perforation/ Avoidance of invasive procedures 3 3C 2A 2 10CA
Fabry Disease
OMIM: 301500
Report
GLA End stage organ disease/ERT (classic males) 2 3E 1A 2 8EA
End stage organ disease/ERT (late on-set males) 2 3E 1A 2 8EA
End stage organ disease/ERT (females) 2 3E 1A 2 8EA
Stroke prevention/aspirin (classic male) 2 2E 0B 3 7EB
Stroke prevention/aspirin (late onset male) 2 2E 0B 3 7EB
Stroke prevention/aspirin (female) 2 2E 0B 3 7EB
Factor V Leiden, Heterozygous
OMIM: 188055
Report
F5 VTE/Assessment for VTE risk factors 3 2C IN N/A IN
VTE/Avoid estrogen-containing compounds that exacerbate VTE risk 3 2C 2B 2 9CB
VTE/Pharmacological prophylaxis 3 2C 0A 1 6CA
Factor V Leiden, Homozygous (Includes compound het FVL + prothrombin G20210A)
OMIM: 188055
Report
F5 VTE/Assessment for VTE risk factors 3 2C IN N/A IN
VTE/Avoid estrogen containing compounds that exacerbate VTE risk 3 2C 2D 3 10CD
VTE/Pharmacological prophylaxis for pregnant women 3 2C 2B 2 9CB
VTE/Pharmacological prophylaxis for men and non-pregnant women 3 2C 0D 2 7CD
Familial Adenomatous Polyposis
OMIM: 175100
Report
APC Colorectal Cancer/Colectomy 2 3A** 2B 1 8AB
Cardiomyopathy, Familial Hypertrophic, 4
OMIM: 115197
Report
MYBPC3 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 1
OMIM: 192600
Report
MYH7 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 7
OMIM: 613690
Report
TNNI3 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 2
OMIM: 115195
Report
TNNT2 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 3
OMIM: 115196
Report
TPM1 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 8
OMIM: 608751
Report
MYL3 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 11
OMIM: 612098
Report
ACTC1 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 6
OMIM: 600858
Report
PRKAG2 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Cardiomyopathy, Familial Hypertrophic, 10
OMIM: 608758
Report
MYL2 Sudden cardiac death/ICD 3 2E 2B 2 9EB
Familial Mediterranean Fever (AD)
OMIM: 134610
Report
MEFV Recurrent serositis/Colchicine 1 0D 3C 2 6DC
Amyloidosis/Colchicine 1 0D 3C 2 6DC
Joint problems/Colchicine 1 0D 3C 2 6DC
Familial Mediterranean Fever (AR)
OMIM: 249100
Report
MEFV Recurrent serositis/Colchicine 2 3C 3A 2 10CA
Amyloidosis/Colchicine 2 2C 3B 2 9CB
Joint problems/Colchicine 2 3C 3A 2 10CA
Familial Papillary Renal Cell Carcinoma 1
OMIM: 605074
Report
MET Morbidity/mortality associated with papillary renal cell carcinoma/Periodic surveillance via renal CT imaging 2 3C 3E 2 10CE
Familial Thoracic Aortic Aneurysms and Dissections
OMIM: N/A
Report
FBN1 Clinically significant aortic aneurysm/Aortic surveillance 3 2D 3C** 3 11DC
Aortic dilation progression/Beta blockers 3 2D 3C 3 11DC
Familial Thoracic Aortic Aneurysms and Dissections
OMIM: N/A
Report
TGFBR1 Clinically significant aortic aneurysm/Aortic surveillance 3 2D 3C** 3 11DC
Aortic dilation progression/Beta blockers 3 2D 3C 3 11DC
Familial Thoracic Aortic Aneurysms and Dissections
OMIM: N/A
Report
TGFBR2 Clinically significant aortic aneurysm/Aortic surveillance 3 2D 3C** 3 11DC
Aortic dilation progression/Beta blockers 3 2D 3C 3 11DC
Familial Thoracic Aortic Aneurysms and Dissections
OMIM: N/A
Report
SMAD3 Clinically significant aortic aneurysm/Aortic surveillance 3 2D 3C** 3 11DC
Aortic dilation progression/Beta blockers 3 2D 3C 3 11DC
Aortic Aneurysm, Familial Thoracic 6
OMIM: 611788
Report
ACTA2 Clinically significant aortic aneurysm/Aortic surveillance 3 2D 3C** 3 11DC
Aortic dilation progression/Beta blockers 3 2D 3C 3 11DC
Aortic Aneurysm, Familial Thoracic 7
OMIM: 613780
Report
MYLK Clinically significant aortic aneurysm/Aortic surveillance 3 2D 3C** 3 11DC
Aortic dilation progression/Beta blockers 3 2D 3C 3 11DC
Aortic Aneurysm, Familial Thoracic 4
OMIM: 132900
Report
MYH11 Clinically significant aortic aneurysm/Aortic surveillance 3 2D 3C** 3 11DC
Aortic dilation progression/Beta blockers 3 2D 3C 3 11DC
Gaucher Disease, Type I
OMIM: 230800
Report
GBA Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)/Surveillance and initiation of ERT 2 3C 2B 2 9CB
Gaucher Disease, Type III
OMIM: 231000
Report
GBA Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)/Surveillance and initiation of ERT 2 3C 2B 2 9CB
Gaucher Disease, Type IIIC
OMIM: 231005
Report
GBA Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease)/Surveillance and initiation of ERT 2 3C 2B 2 9CB
Glycogen storage disease II (GSD2)
OMIM: 232300
Report
GAA Musculoskeletal morbidity/Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.) 2 3C 1B 3 9CB
Musculoskeletal morbidity/Enzyme replacement therapy 2 3C 2B 2 9CB
Impaired pulmonary function/Enzyme replacement therapy 2 3C 2B 2 9CB
Severe or life-threatening infections/Vaccination and aggressive prevention/treatment of infections 2 0D 1D 3 6DD
Glycogen storage disease V (GSD5)
OMIM: 608455
Report
PYGM Rhabdomyolysis, muscle damage, and fixed contractions/Training for an appropriate exercise regimen 1 3E 2C 3 9EC
Hemochromatosis, Type 1
OMIM: 235200
Report
HFE (C282Y Homozygotes only) Clinically apparent disease/Monitoring ferritin levels 2 2A 3B 3 10AB
Clinically apparent disease/Phlebotomy 2 2A 3B 3 10AB
Hemophilia Type A
OMIM: 306700
Report
F8 Severe or prolonged hemorrhage/Development and implementation of comprehensive management plan based on activity levels (Males) 2 3C 2B 2 9CB
Severe or prolonged hemorrhage/Development and implementation of comprehensive management plan based on activity levels (Females) 2 2C 2B 3 9CB
Hemophilia Type B
OMIM: 306900
Report
F9 Severe or prolonged hemorrhage/Development and implementation of comprehensive management plan based on activity levels (Males) 2 3C 2B 2 9CB
Severe or prolonged hemorrhage/Development and implementation of comprehensive management plan based on activity levels (Females) 2 2C 2B 3 9CB
Hereditary Breast and Ovarian Cancer
OMIM: 604370
Report
BRCA1 Breast Cancer/Breast surveillance 2 3A 2A 3 10AA
Breast Cancer/Mastectomy 2 3A 3A 1 9AA
Ovarian Cancer/Oophorectomy 2 2A 3A 1 8AA
Hereditary Breast and Ovarian Cancer
OMIM: 612555
Report
BRCA2 Breast Cancer/Breast surveillance 2 3A 2A 3 10AA
Breast Cancer/Mastectomy 2 3A 3A 1 9AA
Ovarian Cancer/Oophorectomy 2 2A 3A 1 8AA
Hereditary Diffuse Gastric Cancer
OMIM: 137215
Report
CDH1 Gastric cancer/Surveillance 2 3C 1B 2 8CB
Gastric cancer/Risk reducing gastrectomy 2 3C 3A 0 8CA
Breast cancer/Surveillance 2 3C 2B 3 10CB
Breast cancer/Risk reducing mastectomy 2 3C 3B 1 9CB
Breast Cancer
OMIM: 114480
Report
CDH1 Gastric cancer/Surveillance 2 3C 1B 2 8CB
Gastric cancer/Risk reducing gastrectomy 2 3C 3A 0 8CA
Breast cancer/Surveillance 2 3C 2B 3 10CB
Breast cancer/Risk reducing mastectomy 2 3C 3B 1 9CB
Hereditary Hemorrhagic Telangiectasia
OMIM: 187300
Report
ENG Anticipatory treatment to avoid CAVM morbidity/Cerebral MRI 2 2E 2B 3 9EB
Anticipatory treatment to avoid PAVM morbidity/TTCE 2 3E 3B 3 11EB
Hereditary Hemorrhagic Telangiectasia
OMIM: 615506
Report
GDF2 Anticipatory treatment to avoid CAVM morbidity/Cerebral MRI 2 0D 2B 3 7DB
Anticipatory treatment to avoid PAVM morbidity/TTCE 2 0D 3B 3 8DB
Hereditary Hemorrhagic Telangiectasia
OMIM: 175050
Report
SMAD4 Anticipatory treatment to avoid CAVM morbidity/Cerebral MRI 2 1E 2B 3 8EB
Anticipatory treatment to avoid PAVM morbidity/TTCE 2 3E 3B 3 11EB
Hereditary Hemorrhagic Telangiectasia
OMIM: 600376
Report
ACVRL1 Anticipatory treatment to avoid CAVM morbidity/Cerebral MRI 2 1E 2B 3 8EB
Anticipatory treatment to avoid PAVM morbidity/TTCE 2 2E 3B 3 10EB
Hereditary Neuropathy with Liability to Pressure Palsies (HNLPP)
OMIM: 162500
Report
PMP22 Neuropathy/Circumstances to avoid 1 3C 1C 3 8CC
Hereditary Paraganglioma-Pheochromocytoma Syndrome (PGL1)
OMIM: 168000
Report
SDHD Paraganglioma development/Surveillance 2 3C 2C 3 10CC
Hereditary Paraganglioma-Pheochromocytoma Syndrome (PGL2)
OMIM: 601650
Report
SDHAF2 Paraganglioma development/Surveillance 2 2C 2C 3 9CC
Hereditary Paraganglioma-Pheochromocytoma Syndrome (PGL3)
OMIM: 605373
Report
SDHC Paraganglioma development/Surveillance 2 2C 2C 3 9CC
Hereditary Paraganglioma-Pheochromocytoma Syndrome (PGL4)
OMIM: 115310
Report
SDHB Paraganglioma development/Surveillance 2 3C 2C 3 10CC
Hypercholesterolemia, Familial
OMIM: 143890
Report
LDLR High cholesterol/Statins 2 3C 3A 3 11CA
Hypercholesterolemia, Autosomal Dominant, Type B
OMIM: 144010
Report
APOB High cholesterol/Statins 2 3C 3A 3 11CA
Hypercholesterolemia, Autosomal Dominant, 3
OMIM: 603776
Report
PCSK9 High cholesterol/Statins 2 3C 3A 3 11CA
Homocystinuria due to Cystathionine Beta-Synthase Deficiency
OMIM: 236200
Report
CBS (Pyridoxine responsive) Thromboembolism/Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements) 2 2C 3C 2 9CC
(Pyridoxine responsive) Systemic manifestations (includes CNS disease, skeletal findings, and ocular findings)/Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements) 2 3C 1C 2 8CC
(Pyridoxine responsive) Thromboembolism/Prophylactic anti-coagulation in pregnancy 2 2C 2C 2 8CC
(Pyridoxine non-responsive) Thromboembolism/Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements) 2 2C 2C 2 8CC
(Pyridoxine non-responsive) Systemic manifestations (includes CNS disease, skeletal findings, and ocular findings)/Dietary modifications (includes pyridoxine, methionine-restriction, betaine, folate, and B12 supplements) 2 3C 1C 2 8CC
(Pyridoxine non-responsive) Thromboembolism/Prophylactic anti-coagulation in pregnancy 2 2C 2C 2 8CC
Homozygous Familial Hypercholesterolemia (HoFH)
OMIM: N/A
Report
LDLR APOB PCSK9 High cholesterol/Statins 2 3C 3A 3 11CA
High cholesterol/LDL apheresis 2 3C 3B 2 10CB
Hyperparathyroidism 2 (HPRT2); includes Hyperparathyroidism 1 (HPRT1) and Parathyroid Carcinoma Report CDC73 Morbidity from primary hyperparathyroidism/Surveillance of parathyroid hormone and calcium 2 3C 3C 3 11CC
Complications of osseous fibromas/Surveillance with panoramic radiograph 1 2C 2C 3 8CC
Morbidity from advanced renal lesions/Surveillance with renal ultrasound 2 2C 2C 3 9CC
Juvenile Polyposis Syndrome
OMIM: 174900
Report
SMAD4 BMPR1A GI Cancer/Endoscopic Surveillance 2 3C 3E 2 10CE
Juvenile Polyposis/Hereditary Hemorrhagic Telangiectasia Syndrome
OMIM: 175050
Report
SMAD4 GI Cancer/Endoscopic Surveillance 2 3C 3E 2 10CE
Leiomyomatosis and Renal Cell Cancer
OMIM: 150800
Report
FH Renal Cancer/Surveillance 2 2C 2C 3 9CC
Advanced uterine pathology/Annual GYN Exam 1 3C 2C 3 9CC
Li-Fraumeni Syndrome
OMIM: 151623
Report
TP53 Breast cancer/Cancer-specific or general surveillance 2 3C 2B** 3 10CB
Breast cancer/Prophylactic surgery 2 3C 3C** 1 9CC
Breast cancer/Avoidance of radio therapy 2 3C 2B** 3 10CB
Ovarian cancer/Cancer-specific or general surveillance 2 3C 0C** 3 8CC
Ovarian cancer/Prophylactic surgery 2 3C 3C** 1 9CC
Ovarian cancer/Avoidance of radio therapy 2 3C 2C** 3 10CC
Colorectal cancer/Cancer-specific or general surveillance 2 3C 3C** 2 10CC
Colorectal cancer/Prophylactic surgery 2 3C 3C** 1 9CC
Colorectal cancer/Avoidance of radio therapy 2 3C 2C** 3 10CC
Sarcomas/Cancer-specific or general surveillance 2 3C 2E 3 10CE
Sarcomas/Avoidance of radio therapy 2 3C 2C** 3 10CC
CNS tumors/Cancer-specific or general surveillance 2 3C 1C** 3 9CC
CNS tumors/Avoidance of radio therapy 2 3C 2C** 3 10CC
Adrenocortical tumors/Cancer-specific or general surveillance 2 3C 2E 3 10CE
Adrenocortical tumors/Avoidance of radio therapy 2 3C 2C** 3 10CC
Loeys-Dietz Syndrome 1
OMIM: 609192
Report
TGFBR1 Clinically significant aortic aneurysm/Surveillance 3 3C 3C 3 12CC
Aortic dilation progression/Beta blockers 3 3C 3C 3 12CC
Loeys-Dietz Syndrome 2
OMIM: 610168
Report
TGFBR2 Clinically significant aortic aneurysm/Surveillance 3 3C 3C 3 12CC
Aortic dilation progression/Beta blockers 3 3C 3C 3 12CC
Loeys-Dietz Syndrome 3
OMIM: 613795
Report
SMAD3 Clinically significant aortic aneurysm/Surveillance 3 3C 3C 3 12CC
Aortic dilation progression/Beta blockers 3 3C 3C 3 12CC
Colorectal Cancer, Hereditary Nonpolyposis, Type 8
OMIM: 613244
Report
EPCAM Colorectal Cancer/Surveillance 2 3A** 3A 2 10AA
Endometrial Cancer/Surveillance 2 3A** 1A 2 8AA
Endometrial Cancer/Risk Reducing Surgery 2 3A** 3B 1 9AB
Colorectal Cancer, Hereditary Nonpolyposis, Type 4
OMIM: 614337
Report
PMS2 Colorectal Cancer/Surveillance 2 3A** 3A 2 10AA
Endometrial Cancer/Surveillance 2 3A** 1A 2 8AA
Endometrial Cancer/Risk Reducing Surgery 2 3A** 3B 1 9AB
Colorectal Cancer, Hereditary Nonpolyposis, Type 5
OMIM: 614350
Report
MSH6 Colorectal Cancer/Surveillance 2 3A** 3A 2 10AA
Endometrial Cancer/Surveillance 2 3A** 1A 2 8AA
Endometrial Cancer/Risk Reducing Surgery 2 3A** 3B 1 9AB
Lynch Syndrome 1
OMIM: 120435
Report
MSH2 Colorectal Cancer/Surveillance 2 3A** 3A 2 10AA
Endometrial Cancer/Surveillance 2 3A** 1A 2 8AA
Endometrial Cancer/Risk Reducing Surgery 2 3A** 3B 1 9AB
Colorectal Cancer, Hereditary Nonpolyposis, Type 2
OMIM: 609310
Report
MLH1 Colorectal Cancer/Surveillance 2 3A** 3A 2 10AA
Endometrial Cancer/Surveillance 2 3A** 1A 2 8AA
Endometrial Cancer/Risk Reducing Surgery 2 3A** 3B 1 9AB
Malignant Hyperthermia, Susceptibility To, 1
OMIM: 145600
Report
RYR1 Morbidity from MH event/Avoidance of triggering anesthetics 2 2D 3B 3 10DB
Malignant Hyperthermia, Susceptibility To, 5
OMIM: 601887
Report
CACNA1S Morbidity from MH event/Avoidance of triggering anesthetics 2 2D 3B 3 10DB
Marfan Syndrome
OMIM: 154700
Report
FBN1 Clinically significant aortic aneurysms/Surveillance 3 3C 3B 3 12CB
Aortic dilation progression/Beta blockers 3 3C 3A 3 12CA
Methylmalonic Aciduria Due To Methylmalonyl-CoA Mutase Deficiency
OMIM: 251000
Report
MUT Significant morbidity/Protein restriction (Vitamin B12 responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 responsive) 2 3D 2D 3 10DD
Significant morbidity/Vitamin B12 (Vitamin B12 responsive) 2 3D 2C 3 10DC
Significant morbidity/Protein restriction (Vitamin B12 non-responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 non-responsive) 2 3D 2D 3 10DD
Methylmalonic Aciduria, cblA Type
OMIM: 251100
Report
MMAA Significant morbidity/Protein restriction (Vitamin B12 responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 responsive) 2 3D 2D 3 10DD
Significant morbidity/Vitamin B12 (Vitamin B12 responsive) 2 3D 2C 3 10DC
Significant morbidity/Protein restriction (Vitamin B12 non-responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 non-responsive) 2 3D 2D 3 10DD
Methylmalonic Aciduria, cblB Type
OMIM: 251110
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MMAB Significant morbidity/Protein restriction (Vitamin B12 responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 responsive) 2 3D 2D 3 10DD
Significant morbidity/Vitamin B12 (Vitamin B12 responsive) 2 3D 2C 3 10DC
Significant morbidity/Protein restriction (Vitamin B12 non-responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 non-responsive) 2 3D 2D 3 10DD
Methylmalonic Aciduria And Homocystinuria, cblD Type
OMIM: 277410
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MMADHC Significant morbidity/Protein restriction (Vitamin B12 responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 responsive) 2 3D 2D 3 10DD
Significant morbidity/Vitamin B12 (Vitamin B12 responsive) 2 3D 2C 3 10DC
Significant morbidity/Protein restriction (Vitamin B12 non-responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 non-responsive) 2 3D 2D 3 10DD
Methylmalonyl-CoA Epimerase Deficiency
OMIM: 251120
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MCEE Significant morbidity/Protein restriction (Vitamin B12 responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 responsive) 2 3D 2D 3 10DD
Significant morbidity/Vitamin B12 (Vitamin B12 responsive) 2 3D 2C 3 10DC
Significant morbidity/Protein restriction (Vitamin B12 non-responsive) 2 3D 1C 2 8DC
Significant morbidity/Monitor kidney function (Vitamin B12 non-responsive) 2 3D 2D 3 10DD
Maturity Onset Diabetes of the Young, Type 3 (MODY3)
OMIM: 600496
Report
HNF1A Glycemic control/Sulfonylureas and optimal diabetic control 2 3C 3C 3 11CC
Multiple Endocrine Neoplasia Type 2A
OMIM: 171400
Report
RET Medullary thyroid cancer/Thyroidectomy 2 3C 3A 1 9CA
Pheochromocytoma/Biochemical surveillance 2 3C 3B 3 11CB
Hyperparathyoidism/Biochemical surveillance 1 2C 3B 3 9CB
Familial Medullary Thyroid Cancer (FMTC)
OMIM: 155240
Report
RET Medullary thyroid cancer/Thyroidectomy 2 3C 3A 1 9CA
Pheochromocytoma/Biochemical surveillance 2 3C 3B 3 11CB
Hyperparathyoidism/Biochemical surveillance 1 2C 3B 3 9CB
Multiple Endocrine Neoplasia Type I
OMIM: 131100
Report
MEN1 Morbidity from parathyroid adenoma/Biochemical surveillance 1 3C 3B 3 10CB
Morbidity from other neuroendocrine tumors/Biochemical surveillance 2 3C 2B 3 10CB
Morbidity from other neuroendocrine tumors/Imaging surveillance 2 3C 2B 2 9CB
Multiple Endocrine Neoplasia Type 2B
OMIM: 162300
Report
RET Medullary thyroid cancer/Thyroidectomy 2 3C 3A 1 9CA
Pheochromocytoma/Biochemical surveillance 2 3C 3B 3 11CB
MUTYH-Associated Polyposis
OMIM: 608456
Report
MUTYH Colorectal Cancer/Regular colonoscopy or polypectomy 2 3C 3B 2 10CB
Neurofibromatosis type 1
OMIM: 162200
Report
NF1 Malignant peripheral nerve sheath tumors/Consultation with a provider experienced with NF1 for educational purposes 2 2C 0D 3 7CD
Breast Cancer/Surveillance 2 2C 2B 3 9CB
Neurofibromatosis Type II
OMIM: 101000
Report
NF2 Vestibular schwannoma/MRI and Screening 2 3B** 2B 3 10BB
Ornithine Transcabamylase Deficiency (XL)
OMIM: 311250
Report
OTC Hyperammonemic encephalopathy/Dietary modification (Women) 2 2C 2E 2 8CE
Hyperammonemic encephalopathy/Dietary modification (Men) 2 3C 2E 2 9CE
Hyperammonemic encephalopathy/Nitrogen Scavengers (Women) 2 2C 2E 3 9CE
Hyperammonemic encephalopathy/Nitrogen Scavengers (Men) 2 3C 2E 3 10CE
PAH Deficiency
OMIM: 261600
Report
PAH Suboptimal plasma PHE levels/Optimal dietary and medical management to achieve goal PHE levels (includes PHE restriction, Sapropterin, and LNAAs) 2 3C 3B 2 10CB
Fetal teratogenicity (females only)/Pregnancy management of PHE levels 2 3E 3A 2 10EA
Breast Cancer
OMIM: 114480
Report
PALB2 Breast cancer/Chemoprevention 2 2C 2B 2 8CB
Breast cancer/Mastectomy 2 2C 3B 1 8CB
Breast cancer/Surveillance 2 2C 2B 3 9CB
Pancreatic Cancer, Susceptibility To, 3
OMIM: 613348
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PALB2 Breast cancer/Chemoprevention 2 2C 2B 2 8CB
Breast cancer/Mastectomy 2 2C 3B 1 8CB
Breast cancer/Surveillance 2 2C 2B 3 9CB
Pancreatic cancer/melanoma syndrome
OMIM: 606719
Report
CDKN2A Melanoma morbidity and/or mortality/Skin Surveillance 2 3C 2B 3 10CB
Pancreatic cancer morbidity and/or mortality/Periodic pancreatic imaging 2 2C 1E 3 8CE
Pancreatic cancer morbidity and/or mortality/Smoking cessation and/or avoidance 2 2C 2B 3 9CB
Peutz-Jeghers Syndrome
OMIM: 175200
Report
STK11 Breast cancer/Surveillance 2 3C 2A 3 10CA
Breast cancer/Prophylactic surgery 2 3C 3B 1 9CB
Breast cancer/Chemoprevention 2 3C 2A 2 9CA
Ovarian cancer/Surveillance 2 2A 0B 3 7AB
Ovarian cancer/Prophylactic surgery 2 2A 3B 1 8AB
Colorectal cancer/Surveillance 2 3A 3B 3 11AB
PTEN Hamartoma Tumor Syndrome - Cowden Syndrome
OMIM: 158350
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PTEN Breast cancer/Surveillance 2 3C 2B 3 10CB
Thyroid cancer/Ultrasounds 2 2C 2B 3 9CB
Romano-Ward Long QT Syndromes Type 1
OMIM: 192500
Report
KCNQ1 Sudden cardiac death/Beta blockers 3 2C 2B 3 10CB
Sudden cardiac death/ICD implantation 3 2C 2A 2 9CA
Romano-Ward Long QT Syndromes Type 2
OMIM: 613688
Report
KCNH2 Sudden cardiac death/Beta blockers 3 2C 2B 3 10CB
Sudden cardiac death/ICD implantation 3 2C 2A 2 9CA
Romano-Ward Long QT Syndromes Type 3
OMIM: 603830
Report
SCN5A Sudden cardiac death/Beta blockers 3 2C 0D 3 8CD
Sudden cardiac death/ICD implantation 3 2C 2A 2 9CA
Tuberous Sclerosis Complex
OMIM: 191100
Report
TSC1 SEGA development/mTOR inhibitor treatment 2 2E 2B 2 8EB
Morbidity and mortality from non-SEGA, non-LAM tumors/imaging to detect massses when intervention is effective 2 3E 2B 3 10EB
LAM development in women/mTOR inhibitor treatment 2 2E 2B 2 8EB
Tuberous Sclerosis 2
OMIM: 613254
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TSC2 SEGA development/mTOR inhibitor treatment 2 2E 2B 2 8EB
Morbidity and mortality from non-SEGA, non-LAM tumors/imaging to detect massses when intervention is effective 2 3E 2B 3 10EB
LAM development in women/mTOR inhibitor treatment 2 2E 2B 2 8EB
Von Hippel-Lindau Syndrome
OMIM: 193300
Report
VHL Pheochromocytoma/Surveillance 2 3C 2B 3 10CB
Renal Cell Carcinoma/Surveillance 2 3C 3C 3 11CC
Wilson Disease
OMIM: 277900
Report
ATP7B Liver Disease/Chelation and Zinc Therapy 2 3D 3A 2 10DA
Neuropsychiatric Disease/Chelation and Zinc Therapy 2 3D 3A 2 10DA
*Non-diagnostic, excludes newborn screening & prenatal testing/screening **Final classification upgraded after expert review