ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4985G>T (p.Arg1662Leu)

dbSNP: rs370328209
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468219 SCV000546265 uncertain significance Hypertrophic cardiomyopathy 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1662 of the MYH7 protein (p.Arg1662Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 407198). 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 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.
Color Diagnostics, LLC DBA Color Health RCV001185798 SCV001352094 uncertain significance Cardiomyopathy 2019-09-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with leucine at codon 1662 of the MYH7 protein. Computational prediction tool 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 3/282816 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.
Ambry Genetics RCV002339146 SCV002640402 uncertain significance Cardiovascular phenotype 2021-11-08 criteria provided, single submitter clinical testing The p.R1662L variant (also known as c.4985G>T), located in coding exon 33 of the MYH7 gene, results from a G to T substitution at nucleotide position 4985. The arginine at codon 1662 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a whole exome sequencing (WES) cohort with limited clinical details (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6). Additionally, this alteration was detected in a genome-wide association study (GWAS) for genetic susceptibility of hypertrophic cardiomyopathy (HCM) (Harper AR et al. Nat Genet, 2021 02;53:135-142). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001185798 SCV004239476 uncertain significance Cardiomyopathy 2022-07-25 criteria provided, single submitter clinical testing

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