Submissions for variant NM_000256.3(MYBPC3):c.3467dup (p.Pro1157fs)

dbSNP: rs730880720

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158484	SCV000208419	pathogenic	not provided	2017-04-14	criteria provided, single submitter	clinical testing	Although the c.3467dupA variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Proline 1157, changing it to an Alanine, and creating a premature stop codon at position 12 of the new reading frame, denoted p.Pro1157AlafsX12. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with HCM. In summary, c.3467dupA in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae	RCV000689565	SCV000817221	pathogenic	Hypertrophic cardiomyopathy	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro1157Alafs*12) 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 181156). For these reasons, this variant has been classified as Pathogenic.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002287374	SCV002578130	pathogenic	Left ventricular noncompaction 10	2022-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298180	SCV003989427	pathogenic	Cardiovascular phenotype	2023-03-23	criteria provided, single submitter	clinical testing	The c.3467dupA pathogenic mutation, located in coding exon 31 of the MYBPC3 gene, results from a duplication of A at nucleotide position 3467, causing a translational frameshift with a predicted alternate stop codon (p.P1157Afs*12). This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (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.