ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.969T>G (p.Ile323Met) (rs730880861)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766415 SCV000208711 uncertain significance not provided 2015-09-15 criteria provided, single submitter clinical testing p.Ile323Met (ATT>ATG): c.969 T>G in exon 11 of the MYH7 gene (NM_000257.2). The Ile323Met variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Ile323Met results in a conservative amino acid substitution of one nonpolar amino acid for another, this substitution occurs at a position that is conserved across species. Mutations in nearby residues (Val320Met, Ser322Phe, Ala326Pro) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Ile323Met was absent from the 1000 Genomes database, and the NHLBI ESP Exome Variant Server reports Ile323Met was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, data from ethnically-matched control individuals were not available to assess for a population-specific benign variant. With the clinical and molecular information available at this time, we cannot definitively determine if Ile323Met is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae RCV000817033 SCV000957569 uncertain significance Hypertrophic cardiomyopathy 2019-07-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 323 of the MYH7 protein (p.Ile323Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 181332). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV001185246 SCV001351419 uncertain significance Cardiomyopathy 2019-11-04 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158776 SCV000280382 uncertain significance not specified 2012-05-30 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.Ile323Met (I323M;c.969 T>G) in the MYH7 gene This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. Variation at nearby residues in MYH7 has been associated with cardiomyopathy, supporting the functional importance of this region of the protein: Val320Met, Ser322Phe, Ala326Pro (HGMD via GeneDx). This is a conservative amino acid change from a nonpolar isoleucine to a nonpolar methionine. The isoleucine at codon 323 is conserved across species, according to GeneDx. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging” with a score of 0.475. In total this variant has not been seen in ~6500 individuals from published controls and publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however. (Our patient has Mexican ancestry.) No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). No variation at this codon is present in dbSNP or in 1000 genomes. 1000 genomes contains 66 individuals of Mexican ancestry from Los Angeles, as of January 8, 2013. (Out of 1092 genotypes in phase 1, there are 66 people of Mexican ancestry from LA, 55 Puerto Ricans, 60 Colombians from Medellin, totaling 181 individuals.) GeneDx did not report controls.

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