ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3190+4C>T (rs571457875)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766370 SCV000208156 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing This varaint is denoted c.3190+4 C>T: IVS29+4 C>T in intron 29 of the MYBPC3 gene (NM_000256.3). The c.3190+4 C>T variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Several in silico algorithms predict that this variant destroys the splice donor site in intron 29, resulting in abnormal gene splicing which may lead to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. A nearby intronic mutation c.3190+5 G>A, has been reported in association with HCM (Rodriguez-Garcia M et al., 2010). Other splice site mutations in the MYBPC3 gene have been reported in association with HCM. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000158221 SCV000271993 uncertain significance not specified 2015-10-28 criteria provided, single submitter clinical testing The c.3190+4C>T variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy, but has been identified in 9/16308 South Asian chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs571457875). This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not pre dictive enough to rule out pathogenicity. In summary, the clinical significance of the c.3190+4C>T variant is uncertain.
Invitae RCV000629030 SCV000749940 uncertain significance Hypertrophic cardiomyopathy 2020-08-23 criteria provided, single submitter clinical testing This sequence change falls in intron 29 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs571457875, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181003). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change change disrupts the consensus splice site (PMID: 28679633). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171134 SCV001333815 uncertain significance Cardiomyopathy 2018-07-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV001171134 SCV001358824 likely benign Cardiomyopathy 2019-01-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000158221 SCV001442816 uncertain significance not specified 2020-10-19 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.3190+4C>T 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. 4/4 computational tools predict no significant impact on normal splicing. Experimental evidence supports these predictions demonstrating the variant does not cause significantly altered splicing in a cell-based minigene assay (Ito_2017). The variant allele was found at a frequency of 9.6e-05 in 238768 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (0.00059 vs 0.001), allowing no conclusion about variant significance. c.3190+4C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Headrick_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3330+5G>C; Internal testing). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance while one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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