ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4353+5G>A (rs200436876)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158655 SCV000208590 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing c.4353+5 G>A: IVS31+5 G>A in intron 31 of the MYH7 gene (NM_000257.2). The c.4353+5 G>A variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. While two splice algorithms predict c.4353+5 G>A may negatively impact the splice donor site in intron 31, neither predict this variant results in the loss of the splice donor site. The c.4353+5 G>A variant was observed at a frequency of 0.2%, 1/492 alleles, in individuals of African ancestry by the 1000 Genomes database. Although splice site mutations in the MYH7 gene have been reported in association with cardiomyopathy, the vast majority of mutations in MYH7 are missense changes. With the clinical and molecular information available at this time, we cannot definitively determine if c.4353+5 G>A is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae RCV000704878 SCV000833850 uncertain significance Hypertrophic cardiomyopathy 2018-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 31 of the MYH7 gene. It does not directly change the encoded amino acid sequence of the MYH7 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs200436876, ExAC 0.03%). This variant has been observed in an individual referred for genetic testing for a personal or family history of HCM (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181255). 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 may disrupt the consensus splice site, 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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