Submissions for variant NM_000256.3(MYBPC3):c.98_99del (p.Thr33fs)

dbSNP: rs745811346

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484298	SCV000565268	pathogenic	not provided	2022-07-21	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32034629)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001238841	SCV001411671	pathogenic	Hypertrophic cardiomyopathy	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr33Argfs*15) 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 present in population databases (rs745811346, gnomAD 0.0009%). 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: 418349). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002374881	SCV002689586	pathogenic	Cardiovascular phenotype	2023-07-11	criteria provided, single submitter	clinical testing	The c.98_99delCA pathogenic mutation, located in coding exon 2 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 98 to 99, causing a translational frameshift with a predicted alternate stop codon (p.T33Rfs*15). 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.
Color Diagnostics, LLC DBA Color Health	RCV003532137	SCV004359290	pathogenic	Cardiomyopathy	2024-12-23	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 2 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. This variant has been reported in two related individuals affected with hypertrophic cardiomyopathy (PMID: 32034629). This variant has been identified in 1/241490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.