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]

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Variant: NM_000257.4(MYH7):c.4276G>A (p.Glu1426Lys)

CA014743

43005 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cb5ea8fa-74c0-4d48-9e7b-f510d2a84046

HGVS expressions

NM_000257.4:c.4276G>A

NM_000257.4(MYH7):c.4276G>A (p.Glu1426Lys)

ENST00000355349.4:c.4276G>A

ENST00000355349.3:c.4276G>A

NM_000257.3:c.4276G>A

NR_126491.1:n.861C>T

NC_000014.9:g.23417580C>T

CM000676.2:g.23417580C>T

NC_000014.8:g.23886789C>T

CM000676.1:g.23886789C>T

NC_000014.7:g.22956629C>T

NG_007884.1:g.23082G>A

Uncertain Significance

PP3 PM2 PS4_Supporting

BA1 BS3 BS1 PS3 PS1 PP1 PM6 PM1 PM5

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4 (MYH7): c.4276G>A (p.Glu1426Lys) variant has been identified in 5 individuals with DCM (PS4_Supporting; Villard 2005 PMID: 1576978; Shipman 2011 PMID: 21482996; Vikhorev 2017 PMID: 29093449; GeneDx pers. comm.; LMM pers. comm.), including as a de novo occurrence in 1 infant with an additional variant in a cardiomyopathy-associated gene (GeneDx pers. comm.) and in 1 individual with HCM (Walsh 2017 PMID: 27532257; OMGL pers. comm.). Because of the additional variant observed in the individual with the de novo occurrence, the PM6 criterion was not applied. This variant has also been reported in 1 individual with LVNC and reduced ejection fraction and in 1 individual with familial nondilated cardiomyopathy and their child with LVNC (Ambry pers. comm.; Invitae pers. comm). This variant segregated with disease in 2 affected relatives with DCM from 1 family (Villard 2005 PMID: 1576978); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3.

PP3

Tools predict damaging

PM2

Absent from gnomad

PS4_Supporting

TOTAL: 5 probands with DCM (LMM, VIkhorev, Shipman, Villard, genedx), 1 w HCM (Walsh), 1 w LVNC and reduced EF (Invitae), 1 with mild familial nondliated CM (invitae) PS4 _S Lit: 3 probands with DCM (Vikhorev 2017, Shipman 2011, Villard 2005) and 1 with HCM (walsh, non LMM OGML data). Internal data: 1 proband with infantile DCM (LMM) 1 p Infant with DCM, also has a DSP variant (ClinVar Variant ID 163237) on DCM panel. Both parents negative for MYH7 variant, parentage not confirmed. Parents not tested for DSP variant., prrsumed de novo (gene dx) 1 with LVNC w/ reduced EF (Invitae) 1 with mild familial nondilated CM. Variant is also present in son w/ LVNC (Ambry). AS per Heather Zimmerman's email (5/5/20; Per the clinic notes, proband with NYHA Class 1 HF. On most recent echo, patient with LVEF 53%, good exercise tolerance, with appropriate increase in contractability. On past echo proband demonstrated mildly reduced left ventricular contractability with normal left ventricular size and LVEF of 50%; Post-exercise EF of ~55%. Patient also with small restrictive VSD.)

BA1

Absent from gnomad

BS3

ikhorev 2017. Experimental evidence evaluating an impact on protein function demonstrated the variant protein to have faster relaxation kinetics and reduced passive stiffness compared to controls while the degree of cardiomyocyte apoptosis and interstitial cell apoptosis measured for the related sample was considerably increased compared to controls

BS1

Absent from gnomad

PS3

Vikhorev 2017. Experimental evidence evaluating an impact on protein function demonstrated the variant protein to have faster relaxation kinetics and reduced passive stiffness compared to controls while the degree of cardiomyocyte apoptosis and interstitial cell apoptosis measured for the related sample was considerably increased compared to controls

PS1

n/a

PP1

Villard 2005, Seen in segregated in two affected relatives with DCM from one family, not enough to invoke PP1

PM6

genedx proband dcm but had an additional VUS is DSP. Cannot be completely sure that is does not contribute to disease

PM1

does not reside in aa 181-937

PM5

n/a

Approved on: 2021-09-22

Published on: 2021-10-01

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