Submissions for variant NM_000257.4(MYH7):c.1954A>G (p.Arg652Gly)

gnomAD frequency: 0.00001  dbSNP: rs727504239

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628842	SCV000203857	pathogenic	Hypertrophic cardiomyopathy	2015-05-26	criteria provided, single submitter	clinical testing	The p.Arg652Gly variant has been reported in 2 individuals with HCM (Ho 2002, Co to 2012) and was reported to segregate with disease in 6 affected relatives (C. Seidman, pers comm). This variant has also been identified in 1/66208 of Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org), though for diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Arginine (Arg) at position 652 is highly conserved in mammals and across evolut ionarily distant species and the change to glycine (Gly) was predicted to be pat hogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, this variant is located in the last three bases of the exon, which is part of the 5? splice region, though computational tools do not sugges t an impact to splicing. In summary, this variant meets our criteria to be class ified as pathogenic for HCM in an autosomal dominant manner (http://www.partners .org/personalizedmedicine/LMM) based upon segregation studies and its low freque ncy in the general population.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000628842	SCV000223883	pathogenic	Hypertrophic cardiomyopathy	2019-05-29	criteria provided, single submitter	research	This MYH7 Arg652Gly variant has previously been described in several HCM probands (Ho CY et al., 2002; Santos S, et al., 2012; Coto E et al., 2012; Walsh R, et al., 2017). Familial segregation from Ho (2002) identified the variant in 4 affected individuals. We have identified this variant in 2 HCM probands. The first is an isolated HCM case, who has no known family history of disease. The second proband harbours another variant (MYBPC3 Leu994Phe) and both variants have been found to segregate to an affected family member. MYH7 Arg652Gly is absent in the 1000 genomes project (http://www.1000genomes.org/), and is a singleton event (MAF= 0.000008) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). In silico tools SIFT, PolyPhen-2, MutationTaster and CADD predict the variant to be deleterious. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been identified in multiple HCM cases (PS4), is located in a mutational hotspot (PM1), is rare in the general population (PM2), segregates with disease (PP1) and in silico tools predict a deleterious effect (PP3), therefore we classify MYH7 Arg652Gly as "pathogenic".
GeneDx	RCV000223832	SCV000490654	pathogenic	not provided	2016-11-18	criteria provided, single submitter	clinical testing	The R652G variant in the MYH7 gene has been reported previously in association with HCM (Coto et al., 2012; Ho et al., 2002). In the study by Coto et al., R652G was reported in one individual with HCM and was absent in 150 Caucasian controls (Coto et al., 2012). The R652G variant was also reported in one family in which R652G was present in four family members with a HCM phenotype (Ho et al., 2002). R652G results in a non-conservative amino acid substitution of a hydrophilic Arginine with a hydrophobic Glycine at a residue that is conserved across species. In silico analysis predicts R652G is probably damaging to the protein structure/function. Additionally, pathogenic variants in nearby residues (S642L, L658V, M659T, M659I, T660N) have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014), further supporting the functional importance of this region of the protein. Finally, the R652G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret the R652G variant as pathogenic.
Invitae	RCV000628842	SCV000749749	pathogenic	Hypertrophic cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 652 of the MYH7 protein (p.Arg652Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22429680, 22765922, 23549607, 27247418, 27532257, 28790153). ClinVar contains an entry for this variant (Variation ID: 177626). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002415653	SCV002722047	pathogenic	Cardiovascular phenotype	2022-04-13	criteria provided, single submitter	clinical testing	The p.R652G pathogenic mutation (also known as c.1954A>G), located in coding exon 15 of the MYH7 gene, results from an A to G substitution at nucleotide position 1954. The arginine at codon 652 is replaced by glycine, an amino acid with dissimilar 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 was first reported as detected in four affected individuals in one family from a hypertrophic cardiomyopathy (HCM) cohort (Ho CY et al. Circulation, 2002 Jun;105:2992-7). This alteration has also been reported in additional individuals from several HCM cohorts (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Santos S et al. BMC Med. Genet., 2012 Mar;13:17; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10(2)). Another alteration at the same codon, p.R652K (c.1955G>A), has been reported to segregate with HCM in several families (Antoniutti G et al. Genes (Basel), 2022 Feb;13). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479022	SCV004223094	pathogenic	Primary familial hypertrophic cardiomyopathy	2023-11-22	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.1954A>G (p.Arg652Gly) is located near a canonical splice site and results in a non-conservative amino acid change located in the myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251392 control chromosomes (gnomAD). c.1954A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy, including individuals with a positive family history and at least one family in which it segregated with the disease phenotype (e.g. Ho_2002, Olivotto_2008, Coppini_2014, Ross_2017, Walsh_2017, Bagnall_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a significant clustering of missense pathogenic variants has been identified in the myosin head domain in HCM cases (Walsh_2017) and another variant affecting the same amino acid (p.Arg652Lys) has also been identified in individuals with HCM (HGMD database) and has been classified as pathogenic in ClinVar. The following publications have been ascertained in the context of this evaluation (PMID: 36252119, 25524337, 12081993, 30297972, 18533079, 28615295, 27532257). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223832	SCV000280308	likely pathogenic	not provided	2011-12-05	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 p.Arg652Gly (c.1954A>G) Given the case data, segregation, and absence in individuals not selected for having HCM, we consider this variant likely disease causing. The variant has been seen in at least 4 (and possibly 7) unrelated cases of HCM (not including this patient's family). There is moderate segregation data. There is no ClinVar entry (as of December 23rd, 2014). Ho et al (2002) reported the variant in 4 affected family members from a kindred with HCM. These presumably overlap with later reports by this group (Ho et al 2013, Valente et al 2013, Ho et al 2014)). I found an online presentation from a UK genetics group (Aberdeen) that seems to report they saw this variant in one patient with HCM. Santos et al (2012) observed the variant in one of 80 Portuguese individuals with HCM who underwent analysis of 28 HCM-associated genes. Coppini et al (2014) included three patients with HCM and this variant from their Italian cohort in a paper comparing thin and thick filament HCM. This presumably overlaps with this group's prior report(s) (Olivotto et al 2008). It is unclear whether the patients were related or unrelated. Coto et al reported the variant in 1 of 60 HCM patients who underwent MYH7 analysis. The variant was reported online in 1 of 61,081 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 23rd, 2014). Specifically, the variant was observed in 1 of 33589 individuals of European decent. The phenotype of that individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).