Submissions for variant NM_000257.4(MYH7):c.967A>G (p.Ile323Val)

dbSNP: rs730880860

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158774	SCV000208709	uncertain significance	not specified	2013-03-19	criteria provided, single submitter	clinical testing	p.Ile323Val (ATT>GTT): c.967 A>G in exon 11 of the MYH7 gene (NM_000257.2). The Ile323Val variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although, Ile323Val results in a conservative amino acid substitution of one non-polar amino acid with another, it 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. The Ile323Val 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. However, in silico analysis predicts Ile323Val is benign to the protein structure/function.With the clinical and molecular information available at this time, we cannot definitively determine if Ile323Val is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001185245	SCV001351418	uncertain significance	Cardiomyopathy	2023-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 323 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV002516391	SCV003513223	uncertain significance	Hypertrophic cardiomyopathy	2023-08-16	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181331). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 323 of the MYH7 protein (p.Ile323Val).