ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.3612G>C (p.Glu1204Asp)

gnomAD frequency: 0.00009  dbSNP: rs751153777
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243115 SCV000320274 uncertain significance Cardiovascular phenotype 2023-11-23 criteria provided, single submitter clinical testing The p.E1204D variant (also known as c.3612G>C), located in coding exon 24 of the MYH6 gene, results from a G to C substitution at nucleotide position 3612. The glutamic acid at codon 1204 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been detected in an individual reported to have hypertrophic cardiomyopathy and in a sudden death case; however, details were limited and other variants in cardiac-related genes were also detected (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species; however, aspartic acid is the reference amino acid in two 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 variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000647045 SCV000768832 uncertain significance Hypertrophic cardiomyopathy 14 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1204 of the MYH6 protein (p.Glu1204Asp). This variant is present in population databases (rs751153777, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 264374). 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 MYH6 protein function with a negative 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265714 SCV002548231 uncertain significance not specified 2022-05-31 criteria provided, single submitter clinical testing Variant summary: MYH6 c.3612G>C (p.Glu1204Asp) results in a conservative amino acid change located in the Myosin tail of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 248168 control chromosomes. The observed variant frequency is approximately 3.38 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. c.3612G>C has been reported in the literature in an individual who died suddenly of unexplained causes, without strong evidence for causality (Sanchez_2016). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Fulgent Genetics, Fulgent Genetics RCV002500954 SCV002812849 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-09-14 criteria provided, single submitter clinical testing

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