Submissions for variant NM_002471.4(MYH6):c.4798C>A (p.Gln1600Lys)

gnomAD frequency: 0.00001  dbSNP: rs770068575

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193053	SCV001361607	uncertain significance	not specified	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4798C>A (p.Gln1600Lys) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251490 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4798C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001551760	SCV001772333	uncertain significance	not provided	2021-01-26	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
AiLife Diagnostics, AiLife Diagnostics	RCV001551760	SCV002503230	uncertain significance	not provided	2021-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002339487	SCV002634674	uncertain significance	Cardiovascular phenotype	2021-08-11	criteria provided, single submitter	clinical testing	The p.Q1600K variant (also known as c.4798C>A), located in coding exon 31 of the MYH6 gene, results from a C to A substitution at nucleotide position 4798. The glutamine at codon 1600 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003106154	SCV003780185	uncertain significance	Hypertrophic cardiomyopathy 14	2022-03-27	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 928728). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. This variant is present in population databases (rs770068575, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1600 of the MYH6 protein (p.Gln1600Lys).