ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1954A>G (p.Arg652Gly) (rs727504239)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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, 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 ( .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 (, and is a singleton event (MAF= 0.000008) in the Exome Aggregation Consortium dataset ( 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 2019-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 652 of the MYH7 protein (p.Arg652Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs727504239, ExAC 0.002%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 22429680, 28790153, 22765922, 23549607). ClinVar contains an entry for this variant (Variation ID: 177626). 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). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). Two different missense substitutions at this codon (p.Arg652Lys and Arg652Thr ) have been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28138913, 28323875). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been 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 (, 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).

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