Submissions for variant NM_000257.4(MYH7):c.2573G>A (p.Arg858His)

gnomAD frequency: 0.00001  dbSNP: rs2856897

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154296	SCV000203955	likely pathogenic	Hypertrophic cardiomyopathy	2020-09-01	criteria provided, single submitter	clinical testing	The p.Arg858His variant in MYH7 has been identified in at least 4 individuals with HCM (Song 2005, Berge 2014, Walsh 2017, LMM data) and was identified in 3/251456 chromosomes by gnomAD (https://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID #177696). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Of note, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In addition, another variant involving this amino acid, p.Arg858Cys, has been classified as pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg858GHis variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PS4_Supporting, BP4.
GeneDx	RCV001582627	SCV001819497	likely pathogenic	not provided	2022-03-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 177696; ClinVar); This variant is associated with the following publications: (PMID: 22763267, 15563892, 27532257, 27247418, 25351510, 26332594, 24111713, 23403236, 31980526, 34426522, 29300372)
Invitae	RCV000154296	SCV002129368	uncertain significance	Hypertrophic cardiomyopathy	2021-12-30	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 858 of the MYH7 protein (p.Arg858His). This variant is present in population databases (rs2856897, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15563892, 27532257, 31980526). ClinVar contains an entry for this variant (Variation ID: 177696). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002426735	SCV002740312	uncertain significance	Cardiovascular phenotype	2022-10-05	criteria provided, single submitter	clinical testing	The p.R858H variant (also known as c.2573G>A), located in coding exon 20 of the MYH7 gene, results from a G to A substitution at nucleotide position 2573. The arginine at codon 858 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts, and in cohorts not selected for the presence of HCM; however, clinical details were limited (Song L et al. Clin. Chim. Acta. 2005;351:209-16; Golbus JR et al. Circ Cardiovasc Genet. 2012;5:391-9; Berge KE and Leren TP. Clin. Genet. 2014;86:355-60; Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet. Med. 2017;19:192-203; Kars ME et al. Proc Natl Acad Sci U S A. 2021 09;118(36).). This amino acid position is not well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387774	SCV004099854	uncertain significance	not specified	2023-09-15	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2573G>A (p.Arg858His) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2573G>A has been reported in the literature in individuals affected with Cardiomyopathy (example, Song_2005, Gandjbakhch_2010, Olfson_2015, Hou_2020, Stava_2022, Kurzlechner_2022, Dai_2021, Rijdt_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, several missense variants at the Arg858 residue have been reported in individuals with Cardiomyopathy, among which, p.Arg858Cys may be associated with disease (ClinVar ID: 164324), suggesting that this codon may be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 34333030, 22763267, 31980526, 35629155, 26332594, 28759816, 15563892, 35653365). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; Likely pathogenic, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003531981	SCV004356913	likely pathogenic	Cardiomyopathy	2021-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 858 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15563892, 24111713, 25351510, 27532257, 28759816, 31980526). This variant has been identified in 3/251456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg858Cys and p.Arg858Pro, are known to be disease-causing (ClinVar variation ID: 164324, 520277). Based on the available evidence, this variant is classified as Likely Pathogenic.