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.2845G>A (p.Glu949Lys)

CA013144

14093 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1d9bb12c-bae2-4030-a50c-cddb240c95e8

HGVS expressions

NM_000257.4:c.2845G>A

NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ENST00000355349.4:c.2845G>A

ENST00000355349.3:c.2845G>A

NM_000257.3:c.2845G>A

NC_000014.9:g.23423984C>T

CM000676.2:g.23423984C>T

NC_000014.8:g.23893193C>T

CM000676.1:g.23893193C>T

NC_000014.7:g.22963033C>T

NG_007884.1:g.16678G>A

Likely Pathogenic

PP3 PS4_Moderate PM6 PM2

PS2 PS1 PS3 PP1 PM4 PM1 PM5 BA1 BS4 BS3 BS1 BP2 BP7 BP5 BP4 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.2845G>A (p.Glu949Lys) variant in MYH7 has been reported in 12 individuals with HCM (PS4_Moderate; Watkins 1992 PMID:1552912; Walsh 2017 PMID:27532257; Zigova 2018 PMID:28815794; CHEO pers comm.). This variant segregated with disease in 1 affected relative with HCM (Watkins 1992 PMID:1552912); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has been reported as a de novo occurence in 1 child with RCM (PM6; Kapoor 2017 http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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_Moderate; PM6; PM2; PP3

PP3

BayesDel deleterious (0.46)

PS4_Moderate

1 LMM/Walsh HCM proband + 1 CHEO HCM proband + 9 Zigova 2018 HCM probands + 1 Watkins 1992 HCM proband; considered PS4, but minor concern regarding Slovakian founder effects for the 9 Zigova probands, so stayed at moderate.

PM6

Detected in 11 yo boy with RCM. Clinical and genetic analysis of parents was negative. Unclear if paternity confirmed. No PMID for lit. (and note prior paper, also without PMID, indicated 10 unaffected family members without variant--assume this includes the parents) Kapoor M, Das S, Biswas A, Seth S, Bhargava B, Rao VR. Epidemiology of cardiomyopathy – A Clinical and Genetic Study of Restrictive Cardiomyopathy: The EPOCH-R Study. J Pract Cardiovasc Sci 2017;3:143-9. http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf

PM2

absent in gnomAD with ~100X coverage and ~251000 total alleles sequenced per surrounding region

PS2

no such cases

PS1

No such variants reported

PS3

No knock-in mammalian model available

PP1

only 1 meiosis from Watkins 1992

PM4

missense change

PM1

not in head domain (aa181-937)

PM5

E949V is VUS (PM2 only)

BA1

variant is rare

BS4

No failure to segregate with disease reported reported.

BS3

No knock-in mammalian model available

BS1

variant is rare

BP2

No such cases.

BP7

missense change

BP5

no such cases

BP4

BayesDel deleterious (0.46)

PVS1

missense change

Approved on: 2021-03-22

Published on: 2021-08-25

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.