Submissions for variant NM_002471.4(MYH6):c.3343-3C>A

gnomAD frequency: 0.00010  dbSNP: rs565446762

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156432	SCV000206150	uncertain significance	not specified	2014-03-14	criteria provided, single submitter	clinical testing	The 3343-3C>A variant in MYH6 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This variant is located in the 3' splice region. Computational tools suggest a possible impact to splicing. Ho wever, this information is not predictive enough to determine pathogenicity. Add itional information is needed to fully assess the clinical significance of the v ariant.
GeneDx	RCV001529066	SCV001768411	uncertain significance	not provided	2021-09-20	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 supports a deleterious effect on splicing; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 179637; Landrum et al., 2016)
Ambry Genetics	RCV002321651	SCV002609103	likely benign	Cardiovascular phenotype	2023-07-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV002515019	SCV003295219	uncertain significance	Hypertrophic cardiomyopathy 14	2022-04-06	criteria provided, single submitter	clinical testing	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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: 179637). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. This variant is present in population databases (rs565446762, gnomAD 0.006%). This sequence change falls in intron 25 of the MYH6 gene. It does not directly change the encoded amino acid sequence of the MYH6 protein. It affects a nucleotide within the consensus splice site.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529066	SCV001741891	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529066	SCV001954281	likely benign	not provided		no assertion criteria provided	clinical testing