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

CA013144

14093 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2021-03-22

Published on: 2021-08-25

HGVS expressions

NM_000257.4:c.2845G>A
NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)
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
ENST00000355349.4:c.2845G>A
ENST00000355349.3:c.2845G>A
NM_000257.3:c.2845G>A

Likely Pathogenic

• Met criteria codes: PM2 PM6 PS4_Moderate PP3

• Not Met criteria codes: PM5 PM1 PM4 PVS1 BS1 BS4 BS3 BP4 BP7 BP2 BP5 PS1 PS2 BA1 PS3 PP1

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

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

Met criteria codes

• PM2: absent in gnomAD with ~100X coverage and ~251000 total alleles sequenced per surrounding region
• 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
• 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.
• PP3: BayesDel deleterious (0.46)

Not Met criteria codes

• PM5: E949V is VUS (PM2 only)
• PM1: not in head domain (aa181-937)
• PM4: missense change
• PVS1: missense change
• BS1: variant is rare
• BS4: No failure to segregate with disease reported reported.
• BS3: No knock-in mammalian model available
• BP4: BayesDel deleterious (0.46)
• BP7: missense change
• BP2: No such cases.
• BP5: no such cases
• PS1: No such variants reported
• PS2: no such cases
• BA1: variant is rare
• PS3: No knock-in mammalian model available
• PP1: only 1 meiosis from Watkins 1992