ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.3979-11C>G (rs200618133)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000424234 SCV000515490 benign not specified 2016-10-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000424234 SCV001157490 benign not specified 2019-03-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000424234 SCV001360448 benign not specified 2019-08-19 criteria provided, single submitter clinical testing Variant summary: MYH6 c.3979-11C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 227636 control chromosomes in the gnomAD database, including 66 homozygotes. The observed variant frequency is approximately 400 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.3979-11C>G, has been reported in the literature in an individual affected with propionic academia and adult-onset dilated cardiomyopathy (Riemersma_2017), that was possibly a consequence of the patient's metabolic cardiomyopathy. Therefore this report does not support the association of the variant of interest with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (1x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign.

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