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.1318G>A (p.Val440Met)

CA010537

42835 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 531d2edb-6903-4868-a618-28fc1fe18b05

Approved on: 2020-08-12

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.1318G>A

NM_000257.4(MYH7):c.1318G>A (p.Val440Met)

ENST00000355349.4:c.1318G>A

ENST00000355349.3:c.1318G>A

NM_000257.3:c.1318G>A

NC_000014.9:g.23429044C>T

CM000676.2:g.23429044C>T

NC_000014.8:g.23898253C>T

CM000676.1:g.23898253C>T

NC_000014.7:g.22968093C>T

NG_007884.1:g.11618G>A

Likely Pathogenic

PS4_Supporting PP1 PP3 PM1 PM2

BS4 BS3 BS1 BP7 BP5 BP2 BP4 PVS1 PS2 PS1 PS3 BA1 PP4 PM4 PM6 PM5

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.1318G>A (p.Val440Met) variant in MYH7 has been reported in at least 3 individuals with HCM (PS4_Supporting; Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Walsh 2017 PMID:27532257; LMM pers comm.; OMGL pers comm.) and 1 individual with RCM (Invitae pers comm.). This variant segregated with HCM in 3 affected relatives from 3 families (PP1; LMM pers comm.; OMGL pers comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). 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; Walsh 2017 PMID:27532257). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting; PP1; PM2; PM1; PP3.

PS4_Supporting

Conservatively counting 4 probands from ClinGen Internal Data Log. Also lit probands, but those were reported by ClinGen Internal Data Log labs, so I suspect significant overlap. I note that in Walsh 2017 there are 2 reported probands for OMGL, but in internal data log only 1; likewise, 1 HCM proband reported in Bos 2014/Van Driest 2004, but Mayo does not report any probands in internal data log. I conservatively assumed the ClinGen internal data log data was correct, but there may be up to 6 HCM probands.

PP1

2 segs from LMM and 1 from OMGL reported in Internal data log.

PP3

BayesDel Deleterious

PM1

Located in head domain

PM2

not present in gnomAD with good coverage

BS4

PP1 applied.

BS3

No mammalian knock-in model available

BS1

not present in gnomAD with good coverage

BP7

Missense variant

BP5

No such cases reported

BP2

No such cases.

BP4

BayesDel Deleterious

PVS1

Missense substitution

PS2

No de novo cases.

PS1

No such variant reported.

PS3

No mammalian knock-in model available

BA1

not present in gnomAD with good coverage

PP4

Phenotype not specific

PM4

missense substitution

PM6

No de novo cases.

PM5

V440A does not meet Path criteria (PM1, PM2, PP3, PS4_supporting)

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