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.2707G>A (p.Glu903Lys)

CA012894

181202 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8d1a71a4-1e40-49c8-bba8-6eed53cab811

HGVS expressions

NM_000257.4:c.2707G>A
NM_000257.4(MYH7):c.2707G>A (p.Glu903Lys)
NC_000014.9:g.23424122C>T
CM000676.2:g.23424122C>T
NC_000014.8:g.23893331C>T
CM000676.1:g.23893331C>T
NC_000014.7:g.22963171C>T
NG_007884.1:g.16540G>A
ENST00000355349.4:c.2707G>A
ENST00000355349.3:c.2707G>A
NM_000257.3:c.2707G>A

Uncertain Significance

Met criteria codes 4
PP3 PM1 PS4_Supporting PM2_Supporting
Not Met criteria codes 16
PS2 PS1 PS3 BP2 BP5 BP7 BP4 BA1 PP1 PM4 PM6 PM5 PVS1 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The NM_000257.4: c.2707G>A (p.Glu903Lys) variant in MYH7 has been reported in 5 individuals with HCM (PS4_Supporting; Kaski 2009 PMID:20031618; Robyns 2020 PMID:3151393; GeneDx pers. comm.; Invitae pers. comm.; OMGL 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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PM1, PP3.
Met criteria codes
PP3
BayesDel deleterious, revel predicts impact
PM1
Variant falls within specified head domain region
PS4_Supporting
Reported in 5 HCM probands
PM2_Supporting
absent from gnomAD with good coverage
Not Met criteria codes
PS2
No de novo probands reported
PS1
No other c. with same p. reported
PS3
No functional studies available
BP2
no probands met this criteria
BP5
not seen in case with LP/P variant
BP7
missense variant
BP4
BayesDel deleterious, revel predicts impact
BA1
absent from gnomAD with good coverage
PP1
No segregation data available
PM4
Missense change
PM6
No de novo probands reported
PM5
p.E903G (PM1, PP3, PM2) and p.E903Q (PM1, PM2, PS4_supporting) are VUS.
PVS1
Missense variant
BS4
No segregation data available
BS3
No functional studies available
BS1
absent from gnomAD with good coverage
Approved on: 2022-07-31
Published on: 2022-07-31
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