Submissions for variant NM_000257.4(MYH7):c.154G>A (p.Val52Met)

gnomAD frequency: 0.00002  dbSNP: rs730880919

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158876	SCV000208811	uncertain significance	not provided	2016-02-16	criteria provided, single submitter	clinical testing	This variant is denoted Val52Met (aka V52M) at the protein level and c.154 G>A at the cDNA level. The Val52Met variant in the MYH7 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Val52Met results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is not conserved throughout evolution. Additionally, in silico analysis predicts Val52Met is benign to the protein structure/function. Nevertheless, a mutation in a nearby codon (Val59Ile) has been reported in association with HCM, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Val52Met was not observed in at least 5,141 individuals from Caucasian and African American backgrounds, indicating it is not a common benign polymorphism in those populations. Therefore, with the clinical and molecular information available at this time, we cannot unequivocally determine if Val52Met is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001184493	SCV001350472	uncertain significance	Cardiomyopathy	2019-11-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 52 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). 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251448 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.
CeGaT Center for Human Genetics Tuebingen	RCV000158876	SCV002545165	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MYH7: PM2, BP4
Ambry Genetics	RCV002399576	SCV002705154	likely benign	Cardiovascular phenotype	2022-02-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515079	SCV003245136	uncertain significance	Hypertrophic cardiomyopathy	2024-11-26	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 52 of the MYH7 protein (p.Val52Met). This variant is present in population databases (rs730880919, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32894683). ClinVar contains an entry for this variant (Variation ID: 181398). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001184493	SCV003838776	uncertain significance	Cardiomyopathy	2021-06-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001184493	SCV004843090	uncertain significance	Cardiomyopathy	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 52 of the MYH7 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. 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: 24793961, 32894683). This variant has been identified in 2/251448 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.