Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

Curation History

CA011779

14104 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7b17a8bd-b169-46a1-8efa-b7388c4ecdef

Approved on: 2016-12-15

Published on: 2018-11-16

HGVS expressions

NM_000257.3:c.2155C>T

NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

NC_000014.9:g.23425971G>A

CM000676.2:g.23425971G>A

NC_000014.8:g.23895180G>A

CM000676.1:g.23895180G>A

NC_000014.7:g.22965020G>A

NG_007884.1:g.14691C>T

NM_000257.4:c.2155C>T

ENST00000355349.3:c.2155C>T

Pathogenic

PS3 PS4 PS2 PP3 PM2 PM5 PM1 PP1_Strong

Evidence Links 11

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.2155C>T (p.Arg719Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; PMID:22429680; PMID:23816408; PMID:12707239; PMID:19645038; PMID:27532257; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059419.5 ), including 1 de novo occurrence (PS2; 10957787). This variant was found to segregate with disease in 8 affected family members (PP1_Strong; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; SHaRe consortium, PMID: 30297972). A mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:24829265). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2156G>A p.Arg719Gln - Variation ID 14107). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS2; PS3; PS4; PP1_ Strong; PM1; PM2; PM5; PP3

PS3

Mice heterozygous for the R719W variant develop progressive concentric hypertrophy. Homozygous mice died within 9 days of birth.

Mice heterozygous for the R719W variant develop progressive concentric hypertrophy. Homozygous mice died within 9 days of birth. PubMed:24829265

PS4

>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5)

Variant identified in 1 proband with HCM PubMed:23816408

Variant identified in 1 proband with HCM PubMed:19645038

Variant identified in 4 probands with HCM PubMed:27532257

Variant identified in 1 proband with HCM PubMed:12707239

Variant identified in 4 probands with HCM PubMed:8282798

Variant identified in 1 proband with HCM PubMed:22429680

Variant identified de novo in 1 proband with HCM PubMed:10957787

Variant identified in 1 proband with HCM PubMed:12974739

Variant identified in 1 proband with HCM PubMed:9822100

PS2

1 de novo occurrence with paternity confirmed

De novo occurrence with paternity confirmed PubMed:10957787

PP3

Tools predict damaging

PM2

Absent from ExAC

PM5

c.2156G>A (p.Arg719Gln) - Variation ID 14107 - Pathogenic by Expert Panel

PM1

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated PubMed:27532257

PP1_Strong

8 segregations (including SHaRe data)

Variant segregated with disease in 1 affected family member PubMed:8282798

Variant segregated with disease in 4 affected family members PubMed:9829907

Variant segregated with disease in 1 affected family member PubMed:12974739

Variant segregated with disease 1 affected family member PubMed:9822100

Curation History

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