Submissions for variant NM_000256.3(MYBPC3):c.905+1G>T

dbSNP: rs767698543

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000694634	SCV000823089	likely pathogenic	Hypertrophic cardiomyopathy	2018-06-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYBPC3-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709743	SCV000840017	likely pathogenic	Hypertrophic cardiomyopathy 4	2018-04-25	criteria provided, single submitter	clinical testing	This c.905+1G>T variant in the MYBP3 gene has not been reported previously nor observed in general population according to gnomad database. This variant is predicted, through disruption of normal mRNA splicing, to cause loss of function of normal protein, which is a suggested disease mechanism for this gene. Based on current evidences, this c.905+1G>T variant in the MYBP3 gene is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001191952	SCV001359894	likely pathogenic	Cardiomyopathy	2019-06-11	criteria provided, single submitter	clinical testing	This variant alters the intron 9 canonical splice donor site of the MYBPC3 gene. Computational splicing tools predict that this variant may have a significant adverse impact on RNA splicing. Although RNA study has not been performed to confirm the prediction, this variant is expected to result in a disrupted protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. 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 available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001843541	SCV002102782	likely pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Has not been published in association with an MYBPC3-related disorder to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 31447099, 19574547)
Ambry Genetics	RCV003163186	SCV003857401	uncertain significance	Cardiovascular phenotype	2023-01-10	criteria provided, single submitter	clinical testing	The c.905+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 9 of the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.