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_000257.3(MYH7):c.2539_2541delAAG (p.Lys847del)

CA012568

42913 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 58966d39-7dea-41df-be75-5371df18e99e

Approved on: 2021-10-05

Published on: 2021-10-05

HGVS expressions

NM_000257.3(MYH7):c.2539_2541delAAG (p.Lys847del)

ENST00000355349.4:c.2539_2541del

ENST00000355349.3:c.2539_2541del

NM_000257.3:c.2539_2541del

NM_000257.4:c.2539_2541del

NC_000014.9:g.23424909_23424911del

CM000676.2:g.23424909_23424911del

NC_000014.8:g.23894118_23894120del

CM000676.1:g.23894118_23894120del

NC_000014.7:g.22963958_22963960del

NG_007884.1:g.15753_15755del

Likely Pathogenic

PP1 PM2 PM4_Supporting PS4

BA1 BP3 BP5 BP2 BS3 BS1 PS3 PM6 PS2

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: c.2539_2541del (p.Lys847del) variant in MYH7 has been reported in >15 individuals with HCM (PS4; Van Driest 2004 PMID:15358028; Santos 2012 PMID:22429680; Kassem 2013 PMID:23233322; Marsiglia 2013 PMID:24093860; Waldmuller 2008 PMID:18258667; Walsh 2017 PMID: 27532257; Ho 2018 PMID: 30297972; Jaaskelainen 2019 PMID: 30775854; LMM pers. comm.; Invitae pers. comm.). This variant segregated with disease in 3 affected individuals with HCM from 2 families(PP1; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v.2.1.1, http://exac.broadinstitute.org,). This variant is a deletion of 1 amino acid at position 847 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PP1; PM2; PM4_Supporting.

PP1

3 segregations from LMM, 2 families

PM2

Absent from gnomad with good coverage

PM4_Supporting

In-frame indel of one aa

PS4

>15 probands with HCM. There are more publications, but did not continue

BA1

Absent from gnomad with good coverage

BP3

In-frame indel in a non-repeat region

BP5

not oberved

BP2

not observed

BS3

none available

BS1

Absent from gnomad with good coverage

PS3

none available

PM6

n/a

PS2

n/a

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