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.427C>T (p.Arg143Trp)

CA014751

164401 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a5d5ca4d-e48c-4e60-8ec0-83141a9d091a

Approved on: 2022-07-30

Published on: 2022-07-30

HGVS expressions

NM_000257.4:c.427C>T

NM_000257.4(MYH7):c.427C>T (p.Arg143Trp)

NC_000014.9:g.23432714G>A

CM000676.2:g.23432714G>A

NC_000014.8:g.23901923G>A

CM000676.1:g.23901923G>A

NC_000014.7:g.22971763G>A

NG_007884.1:g.7948C>T

ENST00000355349.4:c.427C>T

ENST00000355349.3:c.427C>T

NM_000257.3:c.427C>T

Pathogenic

PP1_Strong PS4 PP3 PM2

BS4 BS3 BS1 BP5 BP7 BP4 BP3 PVS1 PS2 PS1 PS3 BA1 PM6 PM1 PM4 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.427C>T (p.Arg143Trp) variant in MYH7 has been identified in >40 individuals with HCM, including 1 individual in which it was observed in the homozygous state (PS4; Mohiddin 2003 PMID: 12820698; Erdmann 2003 PMID: 12974739; Maron 2012 PMID: 21839045; Curila 2012 PMID: 22455086; Liu 2013 PMID: 23711808; Kapplinger 2014 PMID: 24510615; Chiou 2015 PMID: 25086479; Weissler-Snir 2017 PMID: 28193612; Mademont-Soler 2017 PMID: 28771489; Hershkovitz 2019 PMID: 30588760; Gao 2020 PMID: 32344918; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Centenary Institute Sydney pers. comm.) and segregated with disease in >9 affected relatives from three families (Mademont-Soler 2017 PMID: 28771489 GeneDx pers. comm.; OMGL pers. comm.). It was also identified in 2 infants with DCM that had loss of function variants in MYH7 and both variants segregated with DCM in one affected infant sibling (Ambry pers. comm; LMM pers. comm.). This variant has been identified in 0.002% (FAF 95% CI, 2/18394) of East Asian chromosomes and 0.001% (FAF 95% CI, 4/113754) of European chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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 (Kelly 2018 PMID:29300372): PS4; PP1_Strong; PM2; PP3.

PP1_Strong

7 meioses from clinical lab data (5 OMGL and 2 GeneDx), plus 3 additional reported seg in lit but without family structure.

PS4

>40 cases in combined lit and internal data. PM2 technically met (though see FAF vs MAF concerns). If PM2 does not apply, PS4 would not apply.

PP3

BayesDel inconclusive, Revel score shows impact

PM2

gnomad: 7 total alleles, MAF 0.01%, FAF of 0.002%. Meets EP rule of FAF <0.004%, though I note this is the wrong bound, and the MAF is higher than this. Given the body of evidence, I think we're okay, but it is a bit iffy. And if this doesn't apply, PS4 doesn't apply.

BS4

Seen in unaffected relatives in 30588760 (a in pedigree 1, 4 in pedigree 2), but ages unknown.

BS3

No such studies.

BS1

FAF is 0.0019% in EAS subpop

BP5

Cases with alternate molecular basis for disease are either very severe (2 infant onset compound hets with DCM) or we have no details on severity. No real concern given the data we have.

BP7

missense change

BP4

see above

BP3

Missense change

PVS1

Missense change

PS2

n/a

PS1

No such alteration reported

PS3

No such studies

BA1

FAF is 0.0019% in EAS subpop

PM6

n/a

PM1

5' of head domain

PM4

Missense change

PM5

p.R143Q does not meet pathogenic criteria by MYH7 EP rules.[PM2, PS4 (>15 HCM probands in lit)]. Note I do not have shared clinical data for this alteration, if strong segregation data, could get to pathogenic, but that seems unlikely.

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