Submissions for variant NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

gnomAD frequency: 0.00008  dbSNP: rs587782962

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000529602	SCV000564442	pathogenic	Hypertrophic cardiomyopathy	2021-11-30	reviewed by expert panel	curation	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.
Blueprint Genetics	RCV000143923	SCV000188800	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000529602	SCV000203956	pathogenic	Hypertrophic cardiomyopathy	2014-05-08	criteria provided, single submitter	clinical testing	The Arg1053Gln variant in MYH7 has been reported in 1 individual with a dilated left ventrical and impaired systolic function, and was present in 5 additional a ffected family members with clinical features of septal HCM (Karkkainen 2004). I n addition, it has been identified by our laboratory in 1 individual with HCM an d family history of SCD. The variant was absent from large population studies. Arganine (Arg) at position 1053 is highly conserved in evolution and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool cli nically validated by our laboratory. This tool's pathogenic prediction is estima ted to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) bas ed upon segregation studies and absence from controls.
GeneDx	RCV000158590	SCV000208525	pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing	Reported in Finnish patients with HCM and described as the third most common mutation encountered in Finnish patients with HCM (Jskelinen et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15556047, 30775854, 27247418, 27532257, 29300372, 21310275, 33673806, 31737537, 24888384, 20624503, 35626289, 35753512)
Invitae	RCV000529602	SCV000623690	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1053 of the MYH7 protein (p.Arg1053Gln). This variant is present in population databases (rs587782962, gnomAD 0.07%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15556047, 20624503, 24888384, 27247418, 27460395, 27532257). It is commonly reported in individuals of Finnish ancestry (PMID: 15556047, 20624503, 24888384, 27247418, 27460395, 27532257). ClinVar contains an entry for this variant (Variation ID: 155814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000621026	SCV000739917	pathogenic	Cardiovascular phenotype	2022-05-27	criteria provided, single submitter	clinical testing	The p.R1053Q pathogenic mutation (also known as c.3158G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide position 3158. The arginine at codon 1053 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM), including segregating with disease in one family (Kärkkäinen S, Eur. J. Heart Fail. 2004 Dec; 6(7):861-8; Millat G et al. Eur J Med Genet Jul;53:261-7; Walsh R et al. Genet Med, 2017 02;19:192-203; Kelly MA et al. Genet Med, 2018 03;20:351-359; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Costain G et al. JAMA Netw Open, 2020 09;3:e2018109; Yoshinaga M et al. Circ J, 2021 12;86:118-127; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This alteration has also been described as a founder mutation in a Finnish HCM cohort, accounting for approximately 5-8% of MYH7 variants detected (Jääskeläinen P et al. Ann. Med., 2014 Sep;46:424-9; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000529602	SCV002522168	likely pathogenic	Hypertrophic cardiomyopathy	2021-08-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158590	SCV003834096	likely pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149914	SCV003838109	pathogenic	Cardiomyopathy	2022-06-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000529602	SCV004844780	pathogenic	Hypertrophic cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1053 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 30 individuals affected with hypertrophic cardiomyopathy (PMID: 15556047, 20624503, 24888384, 27532257, 29300372, 30775854, 31737537, 33673806, 34615813). It has been described as a founder variant in the Finnish population (PMID: 24888384). It has been shown that this variant segregates with disease in 6 affected individuals in one family (PMID: 15556047). This variant has been identified in 17/282864 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.