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_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

Curation Version - 1.0
Curation History
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CA015727

36642 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 96f084ee-5a31-4783-b4d4-aa2ffe4b4e45

Approved on: 2021-12-09

Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.5135G>A

NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

NC_000014.9:g.23415651C>T

CM000676.2:g.23415651C>T

NC_000014.8:g.23884860C>T

CM000676.1:g.23884860C>T

NC_000014.7:g.22954700C>T

NG_007884.1:g.25011G>A

ENST00000355349.4:c.5135G>A

ENST00000355349.3:c.5135G>A

NM_000257.3:c.5135G>A

NR_126491.1:n.83C>T

Pathogenic

PS4 PM2 PP1_Strong

BP3 BP5 BP2 BP7 BP4 PS3 PS1 PS2 PP3 PM5 PM6 PM4 PM1 PVS1 BA1 BS3 BS4 BS1

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.5135G>A (p.Arg1712Gln) variant has been reported in >30 individuals with HCM (PS4; Miller 2013 PMID: 23054336; Mook 2013 PMID: 23785128; Glotov 2015 PMID: 25892673; Lopes 2015 PMID: 25351510; Helms 2016 PMID: 27688314; Mademont-Soler 2017 PMID: 28771489; Weissler-Snir 2017 PMID: 28193612; van Velzen 2017 PMID: 2879411; van Lint 2019 PMID: 30847666; Tran Vu 2019 PMID: 31308319; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected relatives with HCM in at least 9 families (PP1_strong; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.002% (FAF 95% CI; 6/128842) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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): PS4, PP1_strong, PM2.

PS4

>>15 probands total from clinical labs and lit

PM2

0.0047% (6/128842) in gnomAD. FAF is 0.002%, which technically meets rules as they are, but this rule uses the wrong bound of the CI. However, I still plan on applying PS4 since there are so very many probands--I think it's still significantly increased over controls (and per EP rules, this technically does apply).

PP1_Strong

15 segregations total from OMGL, LMM, and GeneDx

BP3

Missense change

BP5

No usable cases

BP2

1 report in 2151187, but limited clinical details

BP7

Missense change

BP4

BayesDel inconclusive, revel inconclusive

PS3

No mammalian knock-in model

PS1

Arg1712Trp, LP at best

PS2

No de novo cases reported

PP3

BayesDel inconclusive, revel inconclusive

PM5

R1712W is Clingen EP LP (PS4_moderate; PP1_moderate; PM2; PP3)

PM6

No de novo cases reported

PM4

Missense change

PM1

Falls outside head domain

PVS1

Missense change

BA1

0.0047% (6/128842) in gnomAD. FAF is 0.002%

BS3

No mammalian knock-in model

BS4

lit report of 1 nonseg (mook 2013), but very limited details

BS1

0.0047% (6/128842) in gnomAD. FAF is 0.002%

Curation History

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