Submissions for variant NM_000256.3(MYBPC3):c.1028del (p.Thr343fs)

dbSNP: rs730880686

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158422	SCV000208357	pathogenic	not provided	2021-04-16	criteria provided, single submitter	clinical testing	Reported in ClinVar as a pathogenic variant (ClinVar Variant ID#181114; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29121657, 20474083, 12974739, 31737537)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230998	SCV000284201	pathogenic	Hypertrophic cardiomyopathy	2024-08-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr343Metfs*7) 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: 12974739). This variant is also known as delC343. ClinVar contains an entry for this variant (Variation ID: 181114). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001177094	SCV001341228	pathogenic	Cardiomyopathy	2019-11-24	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 12 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 12974739). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000158422	SCV002501400	pathogenic	not provided	2021-05-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000230998	SCV004848211	pathogenic	Hypertrophic cardiomyopathy	2019-10-14	criteria provided, single submitter	clinical testing	The p.Thr343MetfsX7 variant in MYBPC3 has been identified in at least 3 individuals with HCM (Erdmann 2003, Viswanathan 2017, Marian 2018, Marschall 2019). It was absent from large population studies but has been reported in ClinVar (Variation ID 181114). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 343 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting.