Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

CA013417

155814 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: da96f339-d77d-4caf-afe3-768754b0efca

HGVS expressions

NM_000257.4:c.3158G>A
NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
NC_000014.9:g.23422267C>T
CM000676.2:g.23422267C>T
NC_000014.8:g.23891476C>T
CM000676.1:g.23891476C>T
NC_000014.7:g.22961316C>T
NG_007884.1:g.18395G>A
ENST00000355349.4:c.3158G>A
ENST00000355349.3:c.3158G>A
NM_000257.3:c.3158G>A

Pathogenic

• Met criteria codes: PP1_Strong PS4 PP3 PM2

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

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln) variant in MYH7 has been reported in >35 individuals with hypertrophic cardiomyopathy (HCM), a large proportion of which are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected individuals with HCM in 9 families (PP1_Moderate; Kärkkäinen 2004 PMID:15556047; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.040% (FAF 95% CI; 16/25124) of Finnish chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), but was absent from other populations and is an established Finnish founder variant. 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PP1_Strong; PM2; PP3.

Met criteria codes

• PP1_Strong: Variant segregated with disease in 5 affected relatives with HCM (Kärkkäinen 2004, PMID: 15556047) 2 additional segregation from GeneDx from 2 independent families. 13 segregations from OMGL from 6 families Total of >15 segregation events
• PS4: SUMMARY: This variant has been reported in >35 individuals with hypertrophic cardiomyopathy, and a large proportion are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). Kärkkäinen 2004 (PMID:15556047) - 1 family with a proband with HCM->DCM and segregated in 5 relatives with HCM Jääskeläinen 2014 (PMID:24888384) - 17 probands with HCM Walsh 2017 (PMID:27532257) - 6 probands with HCM from OMGL data LMM Data - 1 proband with HCM SHaRe - 2 probands with HCM (lab not specified, may overlap with other sources) Invitae - 5 probands with HCM Ambry - 2 probands with HCM GeneDx - 4 probands with HCM OMGL - 10 probands with HCM (only considering 4 additional from Walsh paper), 13 segregations from 6 families Literature from ClinVar, HGMD, and Google Scholar from Alamut search string
• PP3: All tools in Alamut, except for AlignGVGD support damaging. Sarcomere polyphony is Path. Amino acid is conserved in vertebrates. REVEL consistent with other in silico tools
• PM2: Variant identified in 0.040% (FAF 95% CI; 16/25124) Finnish chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), but was absent from other analogous populations and is an established Finnish founder variant.

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No de novo data
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No functional data
• PM6: No de novo data
• PM1: Variant is located outside the head domain (aa 181-937)
• PM5: NM_000257.4(MYH7):c.3157C>T (p.Arg1053Trp) in ClinVar as 1 star LP, but no evidence provided and no citations listed. Variant is not in HGMD. No Google scholar hits via Alamut search string. Variant not evaluated further.

Approved on: 2021-11-30

Published on: 2021-12-09