Submissions for variant NM_000257.4(MYH7):c.1588A>G (p.Ile530Val)

dbSNP: rs771831848

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000620076	SCV000740048	uncertain significance	Cardiovascular phenotype	2022-10-24	criteria provided, single submitter	clinical testing	The p.I530V variant (also known as c.1588A>G), located in coding exon 14 of the MYH7 gene, results from an A to G substitution at nucleotide position 1588. The isoleucine at codon 530 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in one individual from a hypertrophic cardiomyopathy (HCM) patient cohort, but clinical details were limited (Murphy SL et al. J Cardiovasc Transl Res 2016;9:153-61). It was also reported in an apparently de novo case in which a patient with characteristics of HCM and athlete's heart exhibited regression of clinical presentation following the cessation of rigorous athletic training (Kebed KY et al. Circ Cardiovasc Imaging, 2015;8:e003312); it is unclear whether this patient was included in the Murphy SL et al. 2016 study. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781633	SCV000919836	uncertain significance	not specified	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The c.1588A>G (p.Ile530Val) in MYH7 gene is a missense variant involves a highly conserved nucleotide located within theMyosin motor domain of beta (or slow) type I cardiac muscle myosin heavy chain 7. The 4/5 in silico tools predict deleterious outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.1588A>G was identified in the control population dataset of gnomAD at a low frequency of 0.000004 (1/ 246008 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.001, suggesting that it is not a common polymorphism. The variant has been reported in at least two individuals with clinical findings suggestive of sarcomeric HCM (Kabed_2015; Homburger_2016), one being a de novo event. Taken together, the variant was classified as VUS-possibly pathogenic, until new information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001186053	SCV001352391	uncertain significance	Cardiomyopathy	2019-10-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 530 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 26162782, 26914223). This variant has been identified in 1/251226 chromosomes 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	RCV001207848	SCV001379215	pathogenic	Hypertrophic cardiomyopathy	2022-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 520309). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 26162782). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs771831848, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 530 of the MYH7 protein (p.Ile530Val).
GeneDx	RCV001576878	SCV001804150	uncertain significance	not provided	2020-01-14	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 520309; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26914223, 27247418, 26162782)