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

dbSNP: rs373746463

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158230	SCV000208165	pathogenic	not provided	2018-03-22	criteria provided, single submitter	clinical testing	The c.3330+5 G>A pathogenic variant has been reported in two individuals with hypertrophic cardiomyopathy (HCM) and was absent from 307 control individuals; however, no additional clinical information or segregation analysis was provided (Wang et al., 2014). In addition, the c.3330+5 G>A variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant destroys the canonical splice donor site in intron 30 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Multiple other downstream splice site variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson P et al., 2014). Furthermore, another pathogenic variant affecting the same splice donor site (c.3330+5 G>C) has previously been reported multiple times in association with HCM and was reported to to segregate with disease in one large family with HCM (Watkins et al., 1995; Alhaj et al., 2013; Nunez et al., 2013; Captur et al., 2014; Lopes et al., 2015). Watkins et al. (1995) also demonstrated that the c.3330+5 G>C variant leads to an aberrant splice transcript due to skipping of exon 30, a shift in the reading frame, and premature termination of translation in exon 31.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795334	SCV000934789	pathogenic	Hypertrophic cardiomyopathy	2023-06-24	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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25132132). ClinVar contains an entry for this variant (Variation ID: 8602). 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: 2921289, 7493025, 25611685, 28679633, 29121657). 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.
Ambry Genetics	RCV002321476	SCV002605813	uncertain significance	Cardiovascular phenotype	2023-03-23	criteria provided, single submitter	clinical testing	The c.3330+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 30 in the MYBPC3 gene. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM), at least some of whom had additional variants in MYBPC3 and other cardiomyopathy-related genes (Wang J et al. Eur J Heart Fail. 2014;16(9):950-7; Norrish G et al. Circulation, 2019 07;140:184-192). Limited minigene assays demonstrated the creation of some abnormal RNA splicing transcripts (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). This nucleotide position is highly 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 variant remains unclear.
OMIM	RCV000009133	SCV000029350	pathogenic	Hypertrophic cardiomyopathy 4	1995-12-01	no assertion criteria provided	literature only