Variant: NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser)

CA013436

42950 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 6a9cd1dc-183f-4897-91e7-0bfc92a4ce1b

HGVS expressions

NM_000257.4:c.3169G>A
NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser)
NC_000014.9:g.23422256C>T
CM000676.2:g.23422256C>T
NC_000014.8:g.23891465C>T
CM000676.1:g.23891465C>T
NC_000014.7:g.22961305C>T
NG_007884.1:g.18406G>A
ENST00000355349.4:c.3169G>A
ENST00000355349.3:c.3169G>A
NM_000257.3:c.3169G>A

Likely Pathogenic

• Met criteria codes: PP3 PM2 PS4

• Not Met criteria codes: PP1 PM6 PM1 PM4 PM5 PVS1 BA1 BS4 BS3 BS1 BP5 BP2 BP7 BP4 PS2 PS1 PS3

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 2 individuals with DCM (PS4; Van Driest 2004 PMID 15358028; Kapplinger 2014 PMID:24510615, Walsh 2017 PMID:27532257; Hazebroek 2018 PMID:24510615; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). Additionally, this variant has also been reported in 1 individual with RCM and AFib, 4 individuals with unspecified heart disease or cardiomyopathy and 1 individual with LVH, CHD and trisomy 21 (Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, 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. ACMG/AMP Criteria applied: PS4, PM2, PP3.

Met criteria codes

• PP3: REVEL = 0.892
• PM2: 2/113762 European chr (0.002%) in gnomAD, FAF 95% CI 0.0003%
• PS4: 11 likely unique probands from literature + 14 likely unique from clinical labs = 25 probands with HCM or RCM.

Not Met criteria codes

• PP1: no segregations reported
• PM6: no de novo occurrences reported
• PM1: not in amino acids amino acids 181-937
• PM4: N/A for missense
• PM5: Other variant at this position (p.Gly1057Asp) is a VUS
• PVS1: N/A for missense
• BA1: 2/113762 European chr in gnomAD
• BS4: no non-segregations reported
• BS3: no functional studies reported
• BS1: 2/113762 European chr in gnomAD
• BP5: 1 individual with pathogenic frameshift in MYBPC3 but not known if individual is more severely affected.
• BP2: One individual reported with pathogenic MYH7 p.(Arg403Trp) variant but not known if disease is more severe.
• BP7: N/A for missense
• BP4: REVEL = 0.892
• PS2: no de novo occurrences reported
• PS1: Same amino acid change has not been reported
• PS3: no functional studies reported

Approved on: 2021-12-09

Published on: 2021-12-09