Submissions for variant NM_000256.3(MYBPC3):c.821+3G>T

dbSNP: rs727503213

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214456	SCV000271998	uncertain significance	not specified	2015-04-01	criteria provided, single submitter	clinical testing	The c.821+3G>T variant in MYBPC3 has been reported in 1 Egyptian individual with HCM as well as in 1 affected relative (Kassem 2013). Data from large population studies is insufficient to assess its frequency. This variant is located in the 5' splice region. Computational tools suggest this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.821+3G>T variant is uncertain.
Center for Human Genetics, University of Leuven	RCV000768509	SCV000886816	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000768509	SCV001236912	pathogenic	Hypertrophic cardiomyopathy	2020-10-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with exon skipping, which introduces a frameshift (PMID: 30645170). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23233322, 30645170, 31513939). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228869). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 7 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a truncated protein product.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000768509	SCV001245071	likely pathogenic	Hypertrophic cardiomyopathy	2019-08-22	criteria provided, single submitter	research	MYBPC3 c.821+3G>T variant has been reported in one HCM case, this proband carried another MYBPC3 variant however, only the c.821+3G>T variant segregated to another affected family member (Kassem HSh, et al., 2013). The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools MaxEntScan and AdaBoost predict that this variant is likely to cause aberrant splicing. We identified this heterozygous variant in a Lebanese child born into a consanguineous family who was diagnosed with severe HCM. Amplification of RNA extracted from septal myectomy tissue and blood showed skipping of exon 7 in MYBPC3 (Singer et al., 2019). Loss of exon 7 is predicted to result in a shift in the reading frame and a subsequent premature stop codon . Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is very rare in the general population (PM2), in silico tools predict aberrant splicing to occur and this was confirmed in RNA studies which showed exon 7 skipping (PS3), and the variant has been reported in a total of 2 unrelated HCM probands (PS4_supporting), therefore we classify MYBPC3 c.821+3G>T as 'likely pathogenic'.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170206	SCV001332758	likely pathogenic	Cardiomyopathy	2017-11-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001556272	SCV001777820	likely pathogenic	not provided	2021-01-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30645170, 23233322, 31513939)
Ambry Genetics	RCV002427004	SCV002678283	likely pathogenic	Cardiovascular phenotype	2021-10-25	criteria provided, single submitter	clinical testing	The c.821+3G>T intronic variant results from a G to T substitution 3 nucleotides after coding exon 7 in the MYBPC3 gene. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with disease in two affected relatives (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80; Singer ES et al. Circ Genom Precis Med, 2019 01;12:e002368; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. However, in silico splice site analysis predicts that this alteration will weaken the native splice donor site, and RNA studies have demonstrated exon 7 skipping in heterozygous individuals (Singer ES et al. Circ Genom Precis Med, 2019 01;12:e002368). Based on the majority of available evidence to date, this variant is likely to be pathogenic.