Evidence Repository
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

Met criteria codes 5
PP1 PP3 PS4_Supporting PM1 PM2
Not Met criteria codes 16
BP7 BP5 BP2 BP4 PS2 PS1 PVS1 PS3 PP4 PM4 PM6 PM5 BA1 BS4 BS3 BS1

Evidence Links 0

Expert Panel

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.
Met criteria codes
PP1
2 segs from LMM and 1 from OMGL reported in Internal data log.
PP3
BayesDel Deleterious
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.
PM1
Located in head domain
PM2
not present in gnomAD with good coverage
Not Met criteria codes
BP7
Missense variant
BP5
No such cases reported
BP2
No such cases.
BP4
BayesDel Deleterious
PS2
No de novo cases.
PS1
No such variant reported.
PVS1
Missense substitution
PS3
No mammalian knock-in model available
PP4
Phenotype not specific
PM4
missense substitution
PM6
No de novo cases.
PM5
V440A does not meet Path criteria (PM1, PM2, PP3, PS4_supporting)
BA1
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
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