Submissions for variant NM_000257.4(MYH7):c.5342G>A (p.Arg1781His)

gnomAD frequency: 0.00002  dbSNP: rs397516246

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000234735	SCV001976480	uncertain significance	Hypertrophic cardiomyopathy	2021-08-25	reviewed by expert panel	curation	The c.5342G>A (p.Arg1781His) variant in MYH7 has been identified in at least 12 individuals with HCM (PS4_Moderate; Lopes 2015 PMID: 25351510; Walsh 2017 PMID: 27532257; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). This variant was identified in 0.00116% (FAF 95% CI; 2/30616) of South Asian 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, due to a lack of evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035959	SCV000059611	uncertain significance	not specified	2019-08-02	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1781His variant in MYH7 has been reported in 4 individuals with HCM (Laredo 2006, Lopes 2015, LMM data) and in 3/129196 European chromosomes as well as 2/30616 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID #43064). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, PP3.
Invitae	RCV000234735	SCV000284285	pathogenic	Hypertrophic cardiomyopathy	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1781 of the MYH7 protein (p.Arg1781His). This variant is present in population databases (rs397516246, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 17125710, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 43064). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000234735	SCV000492983	uncertain significance	Hypertrophic cardiomyopathy	2014-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001550459	SCV001770786	uncertain significance	not provided	2022-01-19	criteria provided, single submitter	clinical testing	Variant reported in multiple unrelated individuals with HCM in the published literature or referred for genetic testing at GeneDx; however, few clinical details were provided and some individuals harbor additional cardiogenetic variants (Laredo et al., 2006; Kaski et al., 2009; Lopes et al., 2015; Homburger et al., 2016; Alamo et al., 2017; Mademont-Soler et al., 2017; Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 43064; ClinVar); This variant is associated with the following publications: (PMID: 27532257, 17125710, 20031618, 25351510, 28606303, 28771489, 27247418, 29687901, 24111713, 32531501)
Ambry Genetics	RCV002345280	SCV002647064	uncertain significance	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The p.R1781H variant (also known as c.5342G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5342. The arginine at codon 1781 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts; however, in some instances clinical detail was limited and co-occurring variants were present, and some reports may overlap (Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292; Azevedo O et al. Am. Heart J., 2020 Apr;226:114-126). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002477078	SCV002792575	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-09-04	criteria provided, single submitter	clinical testing