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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000257.4(MYH7):c.872C>T (p.Ser291Phe)

CA016918

43110 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0aaf0a31-d981-4182-afdc-5044e102fbe5

HGVS expressions

NM_000257.4:c.872C>T

NM_000257.4(MYH7):c.872C>T (p.Ser291Phe)

NC_000014.9:g.23430924G>A

CM000676.2:g.23430924G>A

NC_000014.8:g.23900133G>A

CM000676.1:g.23900133G>A

NC_000014.7:g.22969973G>A

NG_007884.1:g.9738C>T

ENST00000355349.4:c.872C>T

ENST00000355349.3:c.872C>T

NM_000257.3:c.872C>T

Uncertain Significance

PP3 PM1 PS4_Supporting PM2_Supporting

BP5 BP2 BP4 PS3 PS2 PS1 PP1 BA1 PM6 PM5 PM3 BS4 BS3 BS1 BS2

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4 (MYH7): c.872C>T (p.Ser291Phe) variant has been reported in at least 4 individuals with HCM (PS4_Supporting; Lakdawala 2011 PMID:21943931; Marsiglia 2013 PMID:24093860; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; LMM pers. comm.); however, one of these individuals had early-onset HCM (<25 yo) and also carried a second MYH7 variant that is classified as likely pathogenic by this expert panel (p.Lys847del, 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 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. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM2_Supporting; PM1; PP3.

PP3

REVEL score >0.75

PM1

in myosin head domain (residues 181-937)

PS4_Supporting

Identified in at least 4individuals with HCM. One of these observations probably shouldn't count because the likely path MYH7 Lys847del variant was also present (phase not directly determined, but presumably in trans considering the proband's child has the Ser291Phe variant but not the Lys847del variant). That proband had ealier age of onset

PM2_Supporting

absent from the general population -confirmed sufficient coverage of region in gnomad

BP5

no evidence

BP2

I'm not convinced this criteria is appropriate in this instance. The variant was identified in a single individual who also had the MYH7 Lys847del variant, and this individual is reported to have an earlier age of onset. Phase was not directly determined, but presumably in trans considering the proband's child has the Ser291Phe variant but not the Lys847del variant

BP4

REVEL score >0.75

PS3

no evidence

PS2

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

PS1

S291P reported in ClinVar as likely path, but should be a VUS by current guidelines.

PP1

no evidence

BA1

absent from the general population -confirmed sufficient coverage of region in gnomad

PM6

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

PM5

S291P reported in ClinVar as likely path, but should be a VUS by current guidelines.

PM3

n/a

BS4

no evidence

BS3

no evidence

BS1

absent from the general population -confirmed sufficient coverage of region in gnomad

BS2

Unaffected individuals with this variant are younger than expected penetrance age, so not appropriate to apply this criteria based on available evidence.

Approved on: 2022-07-31

Published on: 2022-07-31

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