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.2069T>C (p.Met690Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA011635

42876 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cfe1ae98-ee1a-4601-9028-327d5adaace1

Approved on: 2021-09-22

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.2069T>C

NM_000257.4(MYH7):c.2069T>C (p.Met690Thr)

ENST00000355349.4:c.2069T>C

ENST00000355349.3:c.2069T>C

NM_000257.3:c.2069T>C

NC_000014.9:g.23426057A>G

CM000676.2:g.23426057A>G

NC_000014.8:g.23895266A>G

CM000676.1:g.23895266A>G

NC_000014.7:g.22965106A>G

NG_007884.1:g.14605T>C

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

PP3 PM1 PM2 PS4_Supporting

BP5 BP2 BP7 BP4 BP3 PS2 PS1 PS3 PP1 PVS1 PM6 PM4 PM5 PM3 BA1 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.2069T>C (p.Met690Thr) variant in MYH7 has been reported in at least 3 individuals with HCM (PS4_Supporting; Coppini 2014 PMID:25524337; Homberger 2016 PMID:27247418; Weissler-Snir 2017 PMID:28193612; Walsh 2017 PMID:27532257; CHEO pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). 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). Based on criteria selected, this variant would be classified as likely pathogenic; however the expert panel deemed the bulk of available evidence as being derived from predictive models. Therefore, in the absence of additional case or segregation data, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting; PM2; PM1; PP3.

PP3

conserved and REVEL >0.75

PM1

between amino acids 181-937

PM2

Absent from gnomAD. Good coverage at this position.

PS4_Supporting

Identified in at least 2 probands (appears to be 3)

BP5

not reported with another pathogenic variant

BP2

not reported with another pathogenic variant

BP7

missense variant

BP4

high REVEL score

BP3

missense variant

PS2

no reports of de novo occurrence

PS1

no other variants reported at this codon

PS3

no functional studies

PP1

No segregation data

PVS1

missense variant

PM6

no reports of de novo occurrence

PM4

missense variant

PM5

no other variants reported at this codon

PM3

not reported with another pathogenic variant

BA1

Absent from gnomAD

BS4

No segregation data

BS3

no functional studies

BS1

Absent from gnomAD

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.