Submissions for variant NM_000256.3(MYBPC3):c.1090+1G>A

dbSNP: rs727504269

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000382204	SCV000329717	pathogenic	not provided	2017-05-24	criteria provided, single submitter	clinical testing	The c.1090+1 G>A variant has been reported previously in one individual with HCM from a cohort of 88 Italian patients, and was absent from 200 control chromosomes (Girolami et al., 2006). The c.1090+1 G>A variant is predicted to destroy the canonical splice donor site in intron 12 and to cause abnormal gene splicing, leading 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. Other splice site variants in the MYBPC3 gene associated with HCM have been reported in HGMD, including two other nucleotide changes at the same position (c.1090+1G>T/C) (Stenson et al., 2014). Furthermore, the c.1090+1 G>A variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1090+1 G>A in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae	RCV000691292	SCV000819044	pathogenic	Hypertrophic cardiomyopathy	2022-10-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1090+1G nucleotide in the MYBPC3 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22112859, 22989827, 26914223). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 177668). This variant is also known as IVS12+1G>A. Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16858239, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 12 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).
3billion	RCV002250578	SCV002521762	pathogenic	Hypertrophic cardiomyopathy 4	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000177668). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002453506	SCV002738084	pathogenic	Cardiovascular phenotype	2019-03-26	criteria provided, single submitter	clinical testing	The c.1090+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the MYBPC3 gene. This variant (also known as IVS12+1G>A) has been reported in multiple hypertrophic cardiomyopathy (HCM) cohorts and HCM testing cohorts, although clinical details were limited in some cases (Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Walsh R et al. Genet. Med., 2017 02;19:192-203). Additional variants impacting this donor splice site, c.1090+1G>T and c.1090+1G>C, have also been reported in individuals with HCM (Walsh R et al. Genet. Med., 2017 02;19:192-203; Millat G et al. Clin. Chim. Acta, 2010 Dec;411:1983-91). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000691292	SCV000203914	pathogenic	Hypertrophic cardiomyopathy	2013-03-04	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000382204	SCV001739953	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000382204	SCV001954061	likely pathogenic	not provided		no assertion criteria provided	clinical testing