Submissions for variant NM_000256.3(MYBPC3):c.3490+1G>A

dbSNP: rs397516020

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211824	SCV000059241	pathogenic	Hypertrophic cardiomyopathy	2012-09-10	criteria provided, single submitter	clinical testing	The 3490+1 G>A variant in MYBPC3 has been identified an individual with HCM, seg regated with disease in 4 affected relatives and was absent from 3 unaffected re latives as well as 500 control chromosomes (Rottbauer 1997). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and results in exon skipping, leading to a frameshift and premature termination codon (Rottb auer 1997), which is predicted to lead to an abnormal or absent protein. Loss of function of the MYBPC3 gene is an established mechanism of disease for HCM. In summary, this variant meets our criteria to be classified as pathogenic (http:// pcpgm.partners.org/LMM) based upon the severe impact of the protein.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000211824	SCV000996349	pathogenic	Hypertrophic cardiomyopathy	2017-12-13	criteria provided, single submitter	research	MYBPC3 c.3490+1G>A has been previously reported in at least 4 HCM cases (Walsh R, et al., 2017; Weissler-Snir A, et al., 2017; Ehlermann P, et al., 2008; Rottbauer W, et al., 1997) and was found to segregate to multiple affected individuals in 2 families (Ehlermann P, et al., 2008; Rottbauer W, et al., 1997). We identified this variant in 2 HCM probands (1 North-West European descent, 1 Aboriginal), both of whom have no family history of disease. The variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tool MaxEntScan predicts that the variant will affect splicing. In summary, based on multiple reports in HCM cases, strong segregation in affected individuals, rarity of the variant in the general population and because MYBPC3 loss of function variants are an established cause of HCM, we classify MYBPC3 c.3490+1G>A as 'Pathogenic'.
GeneDx	RCV001551952	SCV001772560	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate abnormal gene splicing with exon skipping (Rottbauer et al., 1997); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42715; Landrum et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28790153, 28193612, 27532257, 9218526)
Invitae	RCV000211824	SCV003440370	pathogenic	Hypertrophic cardiomyopathy	2023-09-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9218526, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42715). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003372600	SCV004087546	pathogenic	Cardiovascular phenotype	2023-07-28	criteria provided, single submitter	clinical testing	The c.3490+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 31 of the MYBPC3 gene. This variant has been detected in unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with HCM in families (Rottbauer W et al. J Clin Invest, 1997 Jul;100:475-82; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10; Walsh R et al. Genet Med, 2017 Feb;19:192-203;Chung H et al. J Cardiovasc Magn Reson, 2021 Mar;23:18; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). RNA studies performed on samples from carriers of this variant have indicated that this variant results in exon skipping (Rottbauer W et al. J Clin Invest, 1997 Jul;100:475-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
OMIM	RCV000009137	SCV000029354	pathogenic	Hypertrophic cardiomyopathy 4	1997-07-15	no assertion criteria provided	literature only