ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1273G>A (p.Gly425Arg) (rs397516097)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766421 SCV000208727 uncertain significance not provided 2015-10-21 criteria provided, single submitter clinical testing p.Gly425Arg (GGG>AGG): c.1273 G>A in exon 14 of the MYH7 gene (NM_000257.2). The G425R mutation in the MYH7 gene has been reported in one Chinese individual diagnosed with HCM and was absent from 120 unrelated age-and sex-matched Chinese control individuals (Song L et al., 2005). Furthermore, the G425R mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G425R is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The G425 residue is highly conserved across species, and consequently, in silico analysis predicts G425R is damaging to the protein structure/function. Additionally, mutations in nearby residues (Q418K, A428V, A430E) have been reported in association with HCM, supporting the functional importance of this region of the protein. In summary, G425R in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Laboratory for Molecular Medicine,Partners HealthCare 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
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158792 SCV000280297 uncertain significance not specified 2015-02-24 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. 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.

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