Submissions for variant NM_000256.3(MYBPC3):c.851+2T>C

gnomAD frequency: 0.00001  dbSNP: rs1194615408

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001188939	SCV001356124	uncertain significance	Cardiomyopathy	2024-01-16	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +2 position of intron 8 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant is likely to cause an in-frame skipping of exon 8 (30 bp-long; amino acids 274-284). To date no pathogenic missense variants have been reported in this exon (ClinVar). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 1/186360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV002284469	SCV002574295	likely pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Identified in an individual in the literature (Van Hout et al., 2020), however, further clinical information was not reported in this population study; Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33087929)
Ambry Genetics	RCV002447021	SCV002681546	likely pathogenic	Cardiovascular phenotype	2017-12-15	criteria provided, single submitter	clinical testing	The c.851+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 8 in the MYBPC3 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.