Submissions for variant NM_000257.4(MYH7):c.4294G>A (p.Val1432Ile)

gnomAD frequency: 0.00005  dbSNP: rs144200285

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000712357	SCV000621970	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Identified in a patient with sudden cardiac death who harbored other cardiogenetic variants (Fadel et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23403236, 33815637)
Athena Diagnostics	RCV000712357	SCV000842831	uncertain significance	not provided	2018-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV000798106	SCV000937705	uncertain significance	Hypertrophic cardiomyopathy	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1432 of the MYH7 protein (p.Val1432Ile). This variant is present in population databases (rs144200285, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 453109). 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 with a positive predictive value of 80%. 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	RCV001176835	SCV001340896	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1432 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 been reported in an individual affected with sudden unexplained death (PMID: 33815637). This variant has been identified in 9/282848 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.
Genetics and Genomics Program, Sidra Medicine	RCV001293072	SCV001434054	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002329246	SCV002629629	uncertain significance	Cardiovascular phenotype	2023-06-28	criteria provided, single submitter	clinical testing	The p.V1432I variant (also known as c.4294G>A), located in coding exon 29 of the MYH7 gene, results from a G to A substitution at nucleotide position 4294. The valine at codon 1432 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506282	SCV002814430	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	2021-08-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001176835	SCV004814381	uncertain significance	Cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1432 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 been reported in an individual affected with sudden unexplained death (PMID: 33815637). This variant has been identified in 9/282848 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.