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.2525G>A (p.Ser842Asn)

CA012535

42912 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 78a71e9d-6e2f-49a7-b413-d705d8bb83ef

Approved on: 2022-07-31

Published on: 2022-07-31

HGVS expressions

NM_000257.4:c.2525G>A

NM_000257.4(MYH7):c.2525G>A (p.Ser842Asn)

NC_000014.9:g.23424923C>T

CM000676.2:g.23424923C>T

NC_000014.8:g.23894132C>T

CM000676.1:g.23894132C>T

NC_000014.7:g.22963972C>T

NG_007884.1:g.15739G>A

ENST00000355349.4:c.2525G>A

ENST00000355349.3:c.2525G>A

NM_000257.3:c.2525G>A

Uncertain Significance

PS4_Supporting PP1 PM1 PM2_Supporting

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

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.2525G>A (p.Ser842Asn) variant in MYH7 has been reported in 4 individuals with HCM (PS4_Supporting; Alfares 2015 PMID:25611685; Walsh 2017 PMID:27532257; CHEO pers. comm.; GeneDx pers. comm.; LMM pers. comm.) and segregated with HCM in 3 affected relatives from 1 family (PP1; GeneDx 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 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. ACMG/AMP Criteria applied: PS4_Supporting; PP1; PM2_Supporting; PM1.

PS4_Supporting

Variant counted in 4 probands: 1 CHEO, 2 GeneDx, 1 LMM and (2 in lit that represent LMM proband)

PP1

Variant segregates in 3 family members of an individual with HCM (GeneDx ClinVar and internal data log)

PM1

Variant located in MYH7 head region (codons 181-937).

PM2_Supporting

Variant absent from gnomAD with good coverage

BP3

variant is missense

BP7

variant is missense

BP5

no evidence

BP2

no evidence

BP4

In silico analysis program don't agree

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS2

no evidence

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

In PMID 28606303: variant reported as a pathogenic variant, for which the amino acid change does not induce an electrical charge change

BA1

Variant absent from gnomAD with good coverage

PP3

In silico analysis program don't agree

PM4

variant is missense

PM6

no evidence

PM5

2 entries in ClinVar: 1 for c.2524A>G, p.Ser842Gly reported as LP, and 1 for c.2525G>C, p.Ser842Thr reported as a VUS. Does not meet our criteria to apply PM5

BS4

no evidence

BS3

In PMID 28606303: variant reported as a pathogenic variant, for which the amino acid change does not induce an electrical charge change

BS1

Variant absent from gnomAD with good coverage

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