Submissions for variant NM_000256.3(MYBPC3):c.2334del (p.Lys779fs)

dbSNP: rs1057518030

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414101	SCV000491390	likely pathogenic	not provided	2016-01-06	criteria provided, single submitter	clinical testing	Although the c.2334delC variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Lysine 779, changing it to a Arginine, creating a premature stop codon at position 43 of the new reading frame, denoted p.Lys779ArgfsX43. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Many other downstream frameshift variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, the c.2334delC variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.2334delC in the MYBPC3 gene is likely pathogenic.
Ambry Genetics	RCV002450953	SCV002738049	pathogenic	Cardiovascular phenotype	2022-02-18	criteria provided, single submitter	clinical testing	The c.2334delC variant, located in coding exon 24 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 2334, causing a translational frameshift with a predicted alternate stop codon (p.K779Rfs*43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV003586179	SCV004260595	pathogenic	Hypertrophic cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys779Argfs*43) 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: 372858). For these reasons, this variant has been classified as Pathogenic.