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]

Variant: NM_000257.4(MYH7):c.1700G>A (p.Arg567His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA011148

42860 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5a1c9715-3b2a-405c-b4cc-42bb1b875907

Approved on: 2021-09-27

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.1700G>A

NM_000257.4(MYH7):c.1700G>A (p.Arg567His)

ENST00000355349.4:c.1700G>A

ENST00000355349.3:c.1700G>A

NM_000257.3:c.1700G>A

NC_000014.9:g.23427773C>T

CM000676.2:g.23427773C>T

NC_000014.8:g.23896982C>T

CM000676.1:g.23896982C>T

NC_000014.7:g.22966822C>T

NG_007884.1:g.12889G>A

Uncertain Significance

PS4_Supporting PP1 PM2

BS4 BS3 BS1 BP3 BP5 BP2 BP7 BP4 PS3 PS2 PS1 BA1 PP3 PM6 PM1 PM4 PM5 PVS1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.1700G>A (p.Arg567His) variant in MYH7 has been identified in 3 individuals with DCM, 1 of whom also had an additional variant in another DCM-associated gene (PS4_Supporting; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; GeneDx pers. comm., LMM pers. comm.) and segregated with disease in 3 affected relatives with DCM from 1 family (PP1; LMM pers. comm.). Additionally, this variant has also been reported in an individual with neuropathy and unspecified heart disease who also had an additional variant in a gene that could account for the clinical features observed (Invitae pers. comm.). This variant has been identified in 0.003% (1/30616) of South Asian chromosomes (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. 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 is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1; PM2.

PS4_Supporting

Total counted probands with DCM = 2 1 proband in literature (probands reported in Walsh and Pugh are most likely the same individual). 4 individuals reported in clinical laboratories - 1 proband with DCM at GeneDX who also had a pathogenic variant in LMNA (not counted as evidence), 1 proband at Invitae with neuropathy and unspecified heart disease who also had a pathogenic TTR variant that may explain disease (not counted as evidence), 2 probands with DCM at LMM (1 of these probands is presumably same individual that is published in Walsh 2017 and Pugh 2014).

PP1

Internal data: LMM reports 3 segregations in 1 family with DCM

PM2

FAF in South Asian population is <0.004%. South Asian population chosen because it is the subpopulation with the highest frequency other than "Other".

BS4

no lack of segregation

BS3

no publications

BS1

PM2 met

BP3

missense variant

BP5

GeneDX reports an individual with DCM who also had a pathogenic variant in LMNA. Invitae reports an individual with neuropathy and unspecified heart disease who also had a pathogenic variant in TTR. Insufficient clinical description and age of onset were provided to apply this rule.

BP2

Not reported in cis or trans with a pathogenic variant in MYH7

BP7

missense variant

BP4

REVEL >0.2

PS3

no publication

PS2

no de novo occurrences reported

PS1

amino acid change has not been reported previously as pathogenic

BA1

Pm2 met

PP3

REVEL <0.75

PM6

no de novo occurrences reported

PM1

between amino acids 181-937, but this region cannot be used to support pathogenicity for other phenotypes than HCM

PM4

missense variant

PM5

NM_000257.4(MYH7):c.1699C>T (p.Arg567Cys) is reported in ClinVar as a VUS by multiple clinical labs

PVS1

missense variant

Curation History

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