Submissions for variant NM_000432.4(MYL2):c.49G>A (p.Val17Met)

gnomAD frequency: 0.00003  dbSNP: rs730880943

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158912	SCV000208847	uncertain significance	not provided	2019-09-23	criteria provided, single submitter	clinical testing	Reported in association with HCM (Ko et al., 2018); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 181424; 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 a deleterious effect; This variant is associated with the following publications: (PMID: 28640247)
Ambry Genetics	RCV000241994	SCV000319925	uncertain significance	Cardiovascular phenotype	2022-03-14	criteria provided, single submitter	clinical testing	The p.V17M variant (also known as c.49G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide position 49. The valine at codon 17 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Ko C et al. Genet Med, 2018 01;20:69-75). 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 alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470133	SCV000549151	uncertain significance	Hypertrophic cardiomyopathy 10	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 17 of the MYL2 protein (p.Val17Met). This variant is present in population databases (rs730880943, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 28640247; internal data). ClinVar contains an entry for this variant (Variation ID: 181424). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 Diagnostics, LLC DBA Color Health	RCV001181615	SCV001346797	uncertain significance	Cardiomyopathy	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 17 of the MYL2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 28640247). This variant has been identified in 5/251464 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.
Fulgent Genetics, Fulgent Genetics	RCV002484987	SCV002786278	uncertain significance	Hypertrophic cardiomyopathy 10; Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy	2022-02-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998369	SCV004845871	uncertain significance	Hypertrophic cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces valine with methionine at codon 17 of the MYL2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/246252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Mayo Clinic Laboratories, Mayo Clinic	RCV000158912	SCV005408397	uncertain significance	not provided	2024-06-26	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000470133	SCV005908208	uncertain significance	Hypertrophic cardiomyopathy 10	2021-12-07	criteria provided, single submitter	clinical testing	The p.Val17Met variant in the MYL2 gene has been previously reported in 1 individual with hypertrophic cardiomyopathy (Ko 2018) and has been submitted to ClinVar (Variation ID: 181424, ncbi.nlm.nih.gov/clinvar/). The p.Val17Met variant has been identified in 5/251464 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/) and 3/3478 chromosomes by the Genome Asia Database (browser.genomeasia100k.org). In silico tools predict that the variant the p.Val17Met variant is deleterious; however, these predictions have not been tested directly. Using ACMG guidelines, this variant was classified as a variant of uncertain significance (ACMG evidence codes used: PP3).