ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3662del (p.Leu1221fs)

dbSNP: rs863225107
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201500 SCV000256173 likely pathogenic Hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
DASA RCV004553097 SCV002097310 pathogenic MYBPC3-related disorder 2022-02-14 criteria provided, single submitter clinical testing The c.3662del;p.(Leu1221Argfs*16) is a null frameshift variant in the MYBPC3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 407321) - PS4_supporting. This variant is not present in population databases (rs863225107, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001853228 SCV002173787 pathogenic Hypertrophic cardiomyopathy 2023-10-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1221Argfs*16) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24093860, 30297972). ClinVar contains an entry for this variant (Variation ID: 217479). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV004649095 SCV005145672 pathogenic Cardiovascular phenotype 2024-05-06 criteria provided, single submitter clinical testing The c.3662delT pathogenic mutation, located in coding exon 33 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 3662, causing a translational frameshift with a predicted alternate stop codon (p.L1221Rfs*16). This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohort (Marsiglia JD et al. Am Heart J, 2013 Oct;166:775-82; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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