Submissions for variant NM_000257.4(MYH7):c.5011A>G (p.Ile1671Val)

gnomAD frequency: 0.00001  dbSNP: rs1456418703

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000707479	SCV000836578	uncertain significance	Hypertrophic cardiomyopathy	2023-05-22	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 583204). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1671 of the MYH7 protein (p.Ile1671Val).
Color Diagnostics, LLC DBA Color Health	RCV001186494	SCV001352934	uncertain significance	Cardiomyopathy	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1671 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 2/251430 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.
GeneDx	RCV001766567	SCV002008897	uncertain significance	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002343575	SCV002645476	uncertain significance	Cardiovascular phenotype	2020-12-09	criteria provided, single submitter	clinical testing	The p.I1671V variant (also known as c.5011A>G), located in coding exon 33 of the MYH7 gene, results from an A to G substitution at nucleotide position 5011. The isoleucine at codon 1671 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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.