ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.4651-3C>A (rs572175190)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599110 SCV000710492 uncertain significance not provided 2018-01-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The c.4651-3 C>A variant has not been published as pathogenic or been reported as benign to our knowledge. The c.4651-3 C>A variant is observed in 7/9634 (0.07%) alleles from individuals of Ashkenazi Jewish background and in 45/271634 (0.02%) global alleles in large population cohorts (Lek et al., 2016). This substitution occurs at a nucleotide that is not conserved. In-silico splice algorithms are inconclusive as to whether this variant impacts the natural splice acceptor site in intron 32 and results in abnormal gene splicing. In the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Invitae RCV000232303 SCV000287430 uncertain significance Familial hypertrophic cardiomyopathy 14 2019-01-07 criteria provided, single submitter clinical testing This sequence change falls in intron 32 of the MYH6 gene. It does not directly change the encoded amino acid sequence of the MYH6 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs572175190, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 239176). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.

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