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.677C>T (p.Ala226Val)

CA10576963

228918 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c355d5e8-f77b-4868-b234-9676541df851

HGVS expressions

NM_000257.4:c.677C>T
NM_000257.4(MYH7):c.677C>T (p.Ala226Val)
NC_000014.9:g.23431640G>A
CM000676.2:g.23431640G>A
NC_000014.8:g.23900849G>A
CM000676.1:g.23900849G>A
NC_000014.7:g.22970689G>A
NG_007884.1:g.9022C>T
ENST00000355349.4:c.677C>T
ENST00000355349.3:c.677C>T
NM_000257.3:c.677C>T

Uncertain Significance

Met criteria codes 3
PM1 PM2_Supporting PS4_Moderate
Not Met criteria codes 21
PS1 PS2 PS3 PP4 PP3 PP1 BA1 PM5 PM4 PM6 PM3 PVS1 BS2 BS3 BS4 BS1 BP7 BP5 BP2 BP4 BP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.677C>T (p.Ala226Val) variant in MYH7 has been identified in at least 7 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID:30297972; Toepfer 2020 PMID:31983222; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. 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 do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2_Supporting; PM1.
Met criteria codes
PM1
Hotspot/est. functional domain (amino acids 181-937) without benign variation
PM2_Supporting
absent in gnomad
PS4_Moderate
1 HCM proband LMM, could overlap with share, to be conservative, don't count, 1 ogml proband, 3 share, 2 invitae probands, 1 gene dx proband all with HCM (7 total)
Not Met criteria codes
PS1
variant not P
PS2
no available data
PS3
no available data
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
BayesDel (metapredictor) indicates tolerated change, revel low score, comp tools mixed, not conserved
PP1
no evidence
BA1
absent in gnomad
PM5
variant not P 226Thr
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
no available data
PM3
no available data
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
no available data
BS4
no evidence
BS1
absent in gnomad
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
no available data
BP2
no available data
BP4
BayesDel (metapredictor) indicates tolerated change, revel low score, comp tools mixed, not conserved
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-07-30
Published on: 2022-07-30
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