Variant: NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp)

CA014718

43003 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 6099dd89-541a-406f-bef7-323e5330bf7a

HGVS expressions

NM_000257.4:c.4258C>T
NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp)
NC_000014.9:g.23417598G>A
CM000676.2:g.23417598G>A
NC_000014.8:g.23886807G>A
CM000676.1:g.23886807G>A
NC_000014.7:g.22956647G>A
NG_007884.1:g.23064C>T
ENST00000355349.4:c.4258C>T
ENST00000355349.3:c.4258C>T
NM_000257.3:c.4258C>T

Likely Pathogenic

• Met criteria codes: PS4 PP3 PM2

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

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp) variant has been reported in >15 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease (PS4_Strong; Van Driest 2004 PMID: 15358028; Millat 2010 PMID: 20624503; Millat 2010 PMID: 20800588; Teirlinck 2012 PMID:23140321; Zou 2013 PMID:23283745; Berge 2014 PMID: 24111713; Ntusi 2016 PMID: 27841901; Homburger 2016 PMID: 27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID: 30297972; Gene Dx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.0003% (FAF 95% CI; 2/113756) of European chromosomes by gnomAD v2.1.1 (PM2; https://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 (PMID:29300372): PS4, PM2, PP3.

Met criteria codes

• PS4: 17 probands total: 12 from literature (including Zou 23283745, could not submit in VCI) +5 (at least from internal lab data) GeneDx: 1 HCM proband (+1 one with path variant in mybpc3 and +1 with son with mild concentric CM who did not have the variant) Invitae: 2 HCM probands LMM: 1 HCM proband OMGL: 1 HCM proband
• PP3: Tools predict damaging. REVEL consistent with other in silico tools.
• PM2: 2/113756 FAF 0.0003%

Not Met criteria codes

• BS4: no evidence of non seg (gene dx proband, not counted her, as no fhx, clinical history included)
• BS3: no fct studies
• BS1: 2/113756 FAF 0.0003%
• BP5: n/a
• BP4: Tools predict damaging
• BA1: 2/113756 FAF 0.0003%
• PS3: no fct studies
• PS2: no de novo occurences
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: n/a
• PM6: no de novo occurences
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: R1420L reported in HGMD as DM?; R1420Q reported as DM. Variants vetted as lp/VUS, not enough criteria to reach pathogenic classification. R1420Q: PM2, PP3 and PP1, PS4_M (LP at best); R1420L: PM2 and PP3

Approved on: 2021-12-09

Published on: 2021-12-09