ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2309-2A>G (rs111729952)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000469704 SCV000059130 pathogenic Hypertrophic cardiomyopathy 2015-08-06 criteria provided, single submitter clinical testing The c.2309-2A>G variant in MYBPC3 has been reported in 2 individuals with HCM an d was absent from 400 control chromosomes (Van Driest 2004, Roncarati 2011). Thi s variant has also been identified by our laboratory in 9 individuals with HCM a nd segregated with disease in two affected family members. This variant is locat ed in the invariant splice region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein . MYBPC3 variants resulting in a heterozygous loss of function are strongly ass ociated with HCM. In summary, this variant meets criteria to be classified as pa thogenic based upon the predicted impact of the variant.
GeneDx RCV000158149 SCV000208084 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The c.2309-2 A>G pathogenic variant in the MYBPC3 gene has been previously reported in association with HCM (Van Driest et al., 2004; Roncarati et al., 2011; Núñez et al., 2013; Rubattu et al., 2016; Walsh et al., 2017) and is not observed in large population cohorts (Lek et al., 2016). Furthermore, the c.2309-2 A>G variant has been identified in multiple other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and has been classified as pathogenic or likely pathogenic by other clinical laboratories in ClinVar (SCV000059130.4, SCV000219755.2, SCV000320566.1, SCV000546443.1; Landrum et al., 2016). This variant has also been shown to segregate with disease in several affected family members tested at GeneDx and an outside laboratory (SCV000059130.4; Landrum et al., 2016). The c.2309-2 A>G variant destroys the canonical splice acceptor site of intron 23 and is predicted to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other pathogenic splice site variants in the MYBPC3 gene have been reported in the Human Gene Muation Database in association with HCM (Stenson et al., 2014).
Ambry Genetics RCV000242393 SCV000320566 pathogenic Cardiovascular phenotype 2018-10-25 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Invitae RCV000469704 SCV000546443 pathogenic Hypertrophic cardiomyopathy 2019-11-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 23 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 21302287, 24704860, 25740977, 27600940, 27483260). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000158149 SCV000748007 pathogenic not provided 2016-12-22 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158149 SCV000927525 pathogenic not provided 2018-02-06 criteria provided, single submitter clinical testing
Color RCV001188336 SCV001355373 pathogenic Cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193930 SCV001363107 pathogenic Primary familial hypertrophic cardiomyopathy 2019-07-01 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.2309-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes canonical a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 149798 control chromosomes. c.2309-2A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Biagini_2014, Calore_2015, Coppini_2014, Girolami_2006, Nunez_2013, Roncarati_2011, VanDriest_2004, Witjas-Paalberends_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.