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

dbSNP: rs111729952

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2022-09-16	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42613; ClinVar); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 34542152, 21302287, 27483260, 27532257, 15519027, 23782526, 27600940, 24704860, 25740977, 11815426, 25351510, 26656175, 25524337, 31589614, 32746448)
Ambry Genetics	RCV000242393	SCV000320566	pathogenic	Cardiovascular phenotype	2021-12-28	criteria provided, single submitter	clinical testing	The c.2309-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 24 in the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (Ambry internal data; Van Driest SL, J. Am. Coll. Cardiol. 2004 Nov; 44(9):1903-10; Roncarati R, J. Cell. Physiol. 2011 Nov; 226(11):2894-900; Lopes LR, Heart 2015 Feb; 101(4):294-301; Rubattu S et al. Int J Mol Sci. 2016;17(8); Walsh R et al Genet Med. 2017;19(2):192-203; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000469704	SCV000546443	pathogenic	Hypertrophic cardiomyopathy	2024-01-21	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. 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 individuals with hypertrophic cardiomyopathy (PMID: 15519027, 21302287, 24704860, 25740977, 27483260, 27600940). ClinVar contains an entry for this variant (Variation ID: 42613). 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.
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 Diagnostics, LLC DBA Color Health	RCV001188336	SCV001355373	pathogenic	Cardiomyopathy	2019-12-30	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the canonical -2 position of intron 23 splice acceptor site of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 21302287, 24704860, 25740977, 27600940, 27483260; Clinvar variation ID 42613). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Genetics and Molecular Pathology, SA Pathology	RCV002466418	SCV002761666	pathogenic	Hypertrophic cardiomyopathy 4	2021-10-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482958	SCV002789180	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-09-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001188336	SCV004239357	pathogenic	Cardiomyopathy	2023-02-01	criteria provided, single submitter	clinical testing