Submissions for variant NM_002471.4(MYH6):c.346-2A>G

gnomAD frequency: 0.00014  dbSNP: rs141187241

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151224	SCV000199086	uncertain significance	not specified	2014-07-24	criteria provided, single submitter	clinical testing	The 346-2A>G variant in MYH6 has not been previously reported in individuals wit h cardiomyopathy, but has been identified in 2/4406 of African American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; db SNP rs141187241). This variant occurs in the invariant region (+/- 1,2) of the s plice consensus sequence and is predicted to cause altered splicing leading to a n abnormal or absent protein. The MYH6 gene has been implicated in the etiology of HCM and DCM (Carniel 2005) as well as ASD (Granados-Riveron 2010) though the overall evidence is modest at this point. To date, 1 splice variant has been re ported in an individual with ASD (Granados-Riveron 2010). In summary, the clinic al significance of the 346-2A>G variant is uncertain.
GeneDx	RCV000766558	SCV000618080	uncertain significance	not provided	2024-03-15	criteria provided, single submitter	clinical testing	Identified in a patient with peripartum cardiomyopathy; however, additional clinical details were not provided (PMID: 26735901); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 33874732, 26735901)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320216	SCV001510992	uncertain significance	Hypertrophic cardiomyopathy 14	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the MYH6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH6 cause disease. This variant is present in population databases (rs141187241, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with peripartum cardiomyopathy (PMID: 26735901, 33874732). ClinVar contains an entry for this variant (Variation ID: 164255). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
New York Genome Center	RCV000766558	SCV002564267	uncertain significance	not provided	2021-10-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453488	SCV002613046	uncertain significance	Cardiovascular phenotype	2024-04-23	criteria provided, single submitter	clinical testing	The c.346-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 3 of the MYH6 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of MYH6 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.