ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3331-2A>C

gnomAD frequency: 0.00001  dbSNP: rs869025469
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208403 SCV000264059 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000270014 SCV000330210 pathogenic not provided 2016-06-16 criteria provided, single submitter clinical testing Although the c.3331-2 A>C variant has not been reported in the literature as a pathogenic variant or as a benignvariant to our knowledge, it destroys the canonical splice acceptor site in intron 30 and is predicted to cause abnormalgene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediatedmRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice sitevariants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014).Furthermore, the c.3331-2 A>C variant was not observed in approximately 6,100 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations.In summary, c.3331-2 A>C in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV001853310 SCV002307689 likely pathogenic Hypertrophic cardiomyopathy 2023-11-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 30 of the MYBPC3 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), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28640247). ClinVar contains an entry for this variant (Variation ID: 222710). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV002321823 SCV002606588 likely pathogenic Cardiovascular phenotype 2022-06-24 criteria provided, single submitter clinical testing The c.3331-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 31 in the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. This variant has been reported in at least two individuals with hypertrophic cardiomyopathy (HCM) (Ambry internal data; Invitae pers. comm.). Additional alterations impacting the same acceptor site (c.3331-2A>G, c.331-1G>A, c.331-1G>C) have been detected in HCM cases (Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Ko C et al. Genet Med, 2018 01;20:69-75; Ho CY et al. Circulation, 2018 10;138:1387-1398). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health RCV003532053 SCV004358635 likely pathogenic Cardiomyopathy 2023-06-21 criteria provided, single submitter clinical testing This variant causes an A to C nucleotide substitution at the -2 position of intron 30 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 2/237500 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.3331-2A>G, c.3331-1G>A and c.3331-1G>C, are known to be disease-causing (ClinVar variation ID: 1878689, 177742 and 519194). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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