Submissions for variant NM_000257.4(MYH7):c.1273G>A (p.Gly425Arg)

dbSNP: rs397516097

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035712	SCV000059363	likely pathogenic	Hypertrophic cardiomyopathy	2019-02-05	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766421	SCV000208727	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Song et al., 2005; Wang et al., 2009; Homburger et al., 2016; Mak et al., 2018); This variant is associated with the following publications: (PMID: 27247418, 19586842, 15563892, 32931854, 29497013, 27532257, 29300372, 34949102, 31856055)
Invitae	RCV000035712	SCV001577617	likely pathogenic	Hypertrophic cardiomyopathy	2022-03-14	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 42834). This missense change has been observed in individuals with clinical features of MYH7-related conditions (PMID: 15563892, 19586842, 27247418, 29497013, 32931854; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 425 of the MYH7 protein (p.Gly425Arg).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158792	SCV000280297	uncertain significance	not specified	2015-02-24	flagged submission	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. p.Gly425Arg (c.1273G>A) in the MYH7 gene. The patient's genetic test results were first reviewed in 2007. They were re-reviewed 1/31/12, 5/15/13, and 17 March 2015. This variant has been reported in at least two cases of HCM (not including our patient) with moderate segregation data and seen in an additional case with a family history of HCM. Song et al (2005) reported the variant in one case of HCM with no segregation data provided. The same group reported a family with four individuals with p.Gly425Arg (Wang et al 2009). Unfortunately that publication is in Chinese, so it is difficult to assess whether it is the same family. We did have a member of our team who reads Chinese review the paper and found that the variant was seen in three family members with HCM and one obligate carrier. There is an assertion in ClinVar as likely pathogenic, from LMM (SCV000059363). They do not note any additional case data and they have not reviewed it since 2010. I contacted them and they shared that they have seen it in one unaffected individual with a family history of HCM, they have not tested any affected individuals. GeneDx also has an assertion in ClinVar, as pathogenic. Other variants at nearby codons have been reported in association with HCM: p.Ala428Val, (Richard et al., 2003; Van Driest et al., 2004), p.Ala430Glu (Morner et al., 2003), and p. Met435Thr (Sawyer et al., 2003). This is a non-conservative amino acid change with a non-polar neutral Glycine replaced with a polar positive Arginine. Glycine at codon 425 is completely conserved in MYH7 across species. In silico analysis (PolyPhen 2) predicts the variant to be probably damaging. In ClinVar LMM notes that their in-house computational tool predicts it to be pathogenic (and is correct 94% of the time) (Jordan et al 2011). The variant was not observed in a total of ~64,120 published and publicly available general population samples, with ~4420 of those matching this patient's ancestry (and the ancestry of the published cases). Specifically, this variant was not observed in 120 published Chinese control individuals (Song et al 2005). This is likely the same 120 control individuals reported by Wang et al (2009). The variant is not reported in dbSNP or 1000 genomes (as of 5/15/13.) There is no variation at codon 425 listed 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 January 21st, 2015). This includes ~4300 Easy Asian individuals.