Submissions for variant NM_000256.3(MYBPC3):c.3190+4C>T

gnomAD frequency: 0.00005  dbSNP: rs571457875

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766370	SCV000208156	uncertain significance	not provided	2023-06-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter splicing; Reported in an individual with cardiomyopathy in published literature who harbored additional cardiogenetic variants (Headrick et al., 2019); This variant is associated with the following publications: (PMID: 28679633, 29121657, 30985088)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000158221	SCV000271993	uncertain significance	not specified	2015-10-28	criteria provided, single submitter	clinical testing	The c.3190+4C>T variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy, but has been identified in 9/16308 South Asian chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs571457875). This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not pre dictive enough to rule out pathogenicity. In summary, the clinical significance of the c.3190+4C>T variant is uncertain.
Invitae	RCV000629030	SCV000749940	uncertain significance	Hypertrophic cardiomyopathy	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 29 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs571457875, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181003). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28679633). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171134	SCV001333815	uncertain significance	Cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171134	SCV001358824	likely benign	Cardiomyopathy	2019-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000158221	SCV001442816	uncertain significance	not specified	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3190+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. Experimental evidence supports these predictions demonstrating the variant does not cause significantly altered splicing in a cell-based minigene assay (Ito_2017). The variant allele was found at a frequency of 9.6e-05 in 238768 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (0.00059 vs 0.001), allowing no conclusion about variant significance. c.3190+4C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Headrick_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3330+5G>C; Internal testing). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance while one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002321662	SCV002609619	uncertain significance	Cardiovascular phenotype	2021-02-16	criteria provided, single submitter	clinical testing	The c.3190+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 29 in the MYBPC3 gene. This variant was reported in an exome cohort, where it was seen in a pediatric dilated cardiomyopathy case who also had PKP2 and TTN variants detected (Headrick AT et al. Mol Genet Genomic Med, 2019 06;7:e593). Minigene assay results did not demonstrate a statistically significant splicing impact (Ito K et al. Proc Natl Acad Sci U S A, 2017 07;114:7689-7694). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.