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

dbSNP: rs730880873

Total submissions: 5

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	2021-08-05	criteria provided, single submitter	clinical testing	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. 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 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 has been observed in an individual with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 181347). This variant is not present in population databases (ExAC no frequency). 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.
Ambry Genetics	RCV002390381	SCV002702805	uncertain significance	Cardiovascular phenotype	2020-08-27	criteria provided, single submitter	clinical testing	The p.I478V variant (also known as c.1432A>G), located in coding exon 13 of the MYH7 gene, results from an A to G substitution at nucleotide position 1432. The isoleucine at codon 478 is replaced by valine, an amino acid with highly similar properties, and is located in the head domain. This variant has been detected in an individual with hypertrophic cardiomyopathy (HCM). The same study reported that cardiac tissue from this patient demonstrated altered myofilament calcium sensitivity; however, the physiological relevance of the reported finding is unclear (Kresin N et al. Front Physiol, 2019 Mar;10:239). A different variant affecting this codon (p.I478N, c.1433T>A) has been reported in HCM cohorts (Walsh R et al. Genet. Med. 2017 02;19(2):192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484986	SCV002787918	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-08-26	criteria provided, single submitter	clinical testing
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).