Submissions for variant NM_002471.4(MYH6):c.3979-11C>G

dbSNP: rs200618133

Total submissions: 10

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	RCV001529649	SCV001157490	benign	not provided	2023-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002056395	SCV002452014	benign	Hypertrophic cardiomyopathy 14	2025-02-02	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001529649	SCV005232857	benign	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529649	SCV001743454	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000424234	SCV001917697	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529649	SCV001928059	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000424234	SCV001951733	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000424234	SCV001975394	benign	not specified		no assertion criteria provided	clinical testing