Submissions for variant NM_000257.4(MYH7):c.5450C>T (p.Ala1817Val)

gnomAD frequency: 0.00001  dbSNP: rs1469786429

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521167	SCV000621421	uncertain significance	not provided	2017-10-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The A1817V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 4/126706 (0.003%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The A1817V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species, and in silico analysis suggests that this variant is probably damaging to the protein structure/function.
Invitae	RCV000550416	SCV000623740	uncertain significance	Hypertrophic cardiomyopathy	2022-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1817 of the MYH7 protein (p.Ala1817Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 452602). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV003150258	SCV003838743	uncertain significance	Cardiomyopathy	2021-09-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372740	SCV004096144	uncertain significance	Cardiovascular phenotype	2023-07-27	criteria provided, single submitter	clinical testing	The p.A1817V variant (also known as c.5450C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5450. The alanine at codon 1817 is replaced by valine, an amino acid with 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.
Color Diagnostics, LLC DBA Color Health	RCV003150258	SCV004359508	uncertain significance	Cardiomyopathy	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1817 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 been identified in 4/282810 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.