Submissions for variant NM_000256.3(MYBPC3):c.3330+5G>T

dbSNP: rs373746463

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000793517	SCV000059232	likely pathogenic	Hypertrophic cardiomyopathy	2012-06-14	criteria provided, single submitter	clinical testing	The 3330+5G>T variant in MYBPC3 has not been previously reported in the literatu re, but has been identified in 1 Caucasian individual and 1 Hispanic individual with HCM out of >3200 probands (>2150 Caucasian and >110 Hispanic) tested by our laboratory. This variant occurs in the 5' splice region. Computational tools su ggest an impact to splicing, though this information is not predictive enough to determine pathogenicity. Another variant at the same position (3330+5G>C) has s hown segregation with disease and causes skipping of exon 30, resulting in a pre mature termination codon that is predicted to lead to a truncated or absent prot ein (Watkins 1995). This variant likely has a similar effect on splicing, but ad ditional studies are needed to establish this with confidence. In summary, addit ional evidence such as with disease and functional effects are required to fully establish the pathogenicity of this variant.
GeneDx	RCV000158457	SCV000208392	likely pathogenic	not provided	2025-01-17	criteria provided, single submitter	clinical testing	Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 25611685, 36264615, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28679633, 7493025, 25132132, 36264615, 37652022, 34461741, 25611685, 23782526, 24704860, 25351510, 28138913)
Ambry Genetics	RCV000248382	SCV000320270	likely pathogenic	Cardiovascular phenotype	2015-09-21	criteria provided, single submitter	clinical testing	The c.3330+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 30 in the MYBPC3 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6194 samples (12388 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, and is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. In addition, alterations at the same position (c.3330+5G>C and c.3330+5G>A) have been reported in association with hypertrophic cardiomyopathy (HCM) (Watkins et al. Nat. Genet.1995 Dec;11(4):434-7; Wang J et al. Eur J Heart Fail. 2014;16(9):950-7). The c.3330+5G>C, alteration segregated with disease in two families, and was reported to result in abnormal splicing leading to skipping of exon 30 and predicted premature protein truncation (Watkins et al. Nat. Genet.1995 Dec;11(4):434-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793517	SCV000932873	pathogenic	Hypertrophic cardiomyopathy	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 30 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42707). 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). This variant disrupts the c.3330+5G nucleotide in the MYBPC3 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 7493025, 25132132, 28679633). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.