ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1432A>G (p.Ile478Val) (rs730880873)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766424 SCV000208740 uncertain significance not provided 2013-06-03 criteria provided, single submitter clinical testing p.Ile478Val (ATC>GTC): c.1432 A>G in exon 15 of the MYH7 gene (NM_000257.2). The Ile478Val variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Ile478Val results in a conservative amino acid substitution of one non-polar residue for another, the Ile478 residue is conserved across species. In addition, other mutations affecting nearby residues (Phe468Leu, Asp469Tyr, Gln475His, Gln475Lys) have been reported in association with DCM, supporting the functional importance of this region of the protein. Furthermore, the Ile478Val 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. With the clinical and molecular information available at this time, we cannot definitively determine if Ile478Val is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae RCV001060119 SCV001224782 uncertain significance Hypertrophic cardiomyopathy 2019-04-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 478 of the MYH7 protein (p.Ile478Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 181347). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158805 SCV000280302 uncertain significance not specified 2013-09-12 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.Ile478Val (c.1432 A>G, I487V) in exon 15 of the MYH7 gene (NM_000257.2) This is a conservative amino acid change with a Grantham score of 29. In silico analysis with PolyPhen-2 predicts the variant to be benign while mutation taster predicts it to be disease causing. The isoleucine at codon 478 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Phe468Leu, Asp469Tyr, Gln475His, Gln475Lys, Asn479Ser, Glu483Lys), per GeneDx summary of HGMD listings and the Seidman's online database. I could not find any variants at the same codon. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 478 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of May 13th, 2014). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of May 13th, 2014).

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