ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.927-2A>G

gnomAD frequency: 0.00003  dbSNP: rs397516082
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000531021 SCV000059333 pathogenic Hypertrophic cardiomyopathy 2019-02-01 criteria provided, single submitter clinical testing The c.927-2A>G variant in MYBPC3 has been identified in several individuals with HCM, segregated with disease in >10 affected relatives, and was absent from 400 control chromosomes (Nimura 1998, Richard 2003, Ehlermann 2008), as well as in two large and broad populations screened NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/). In addition, this variant affects the invariant (-1/-2) positions in the splice consensus sequence, and was confirmed to lead to aberrant splicing in lymphoblast cells from HCM patients with this variant (Nimura 1998). In summary, this variant meets our criteria for pathogenicity (http://pcpgm.partners.org/LMM) based on familial segregation analyses and the impact of the variant.
GeneDx RCV000158322 SCV000208257 pathogenic not provided 2022-01-11 criteria provided, single submitter clinical testing 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 at a significant frequency in large population cohorts (gnomAD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42806; ClinVar); This variant is associated with the following publications: (PMID: 25525159, 30775854, 31006259, 20019025, 7493026, 26914223, 12707239, 18957093, 22574137, 25078086, 26654849, 26358504, 25583989, 26920199, 27532257, 24510615, 25351510, 9562578, 32341788, 31513939, 30847666, 31568572, 31333075, 33757590, 24704860, 33906374, 33673806)
Invitae RCV000531021 SCV000623630 pathogenic Hypertrophic cardiomyopathy 2024-01-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9562578, 22574137, 25078086, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42806). 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 RCV000619499 SCV000740222 pathogenic Cardiovascular phenotype 2021-02-09 criteria provided, single submitter clinical testing The c.927-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 12 in the MYBPC3 gene. This alteration has been previously reported in association with hypertrophic cardiomyopathy (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57 (reported as Int12ASA-2G); Richard P et al. Circulation, 2003 May;107:2227-32 (reported as IVS12–2:a7308g); Ehlermann P et al. BMC Med. Genet., 2008 Oct;9:95; Kuster DW et al. J. Mol. Cell. Cardiol., 2013 Dec;65:59-66; Walsh R et al. Genet. Med., 2017 Feb;19:192-203), and reported to segregate with disease in families (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Ehlermann P et al. BMC Med. Genet., 2008 Oct;9:95; Adalsteinsdottir B et al. Open Heart, 2020 Apr;7:e001220). In addition, haplotype analysis has suggested this alteration to be a founder mutation in Iceland (Adalsteinsdottir B et al. Circulation, 2014 Sep;130:1158-67). 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000609977 SCV000743566 pathogenic Hypertrophic cardiomyopathy 4 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000609977 SCV000744860 pathogenic Hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Center for Human Genetics, University of Leuven RCV000531021 SCV000886752 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158322 SCV000928042 pathogenic not provided 2018-11-07 criteria provided, single submitter clinical testing
Klaassen Lab, Charite University Medicine Berlin RCV000853176 SCV000995891 pathogenic Primary familial hypertrophic cardiomyopathy 2019-07-03 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV000158322 SCV001249489 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000158322 SCV002017654 pathogenic not provided 2019-04-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000853176 SCV002570550 pathogenic Primary familial hypertrophic cardiomyopathy 2022-07-28 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.927-2A>G alters a conserved nucleotide 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: Two predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-06 in 196860 control chromosomes. c.927-2A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Richard_2000, Niimura_1998). These data indicate that the variant is very likely to be associated with disease. Ten 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000609977 SCV003921053 pathogenic Hypertrophic cardiomyopathy 4 2023-10-16 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4,PM2_SUP
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003486553 SCV004239398 pathogenic Cardiomyopathy 2023-03-07 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158322 SCV000280286 pathogenic not provided 2014-07-18 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS11-2A>G Based on the data reviewed below, we consider this variant very likely disease causing. This variant has been seen in at least 7 unrelated published HCM cases, with strong segregation data. It was initially reported in 2 presumably unrelated French families with strong segregation data (Bonne et al 1995). All nine individuals with HCM in one family had the variant as did all 20 individuals with HCM in the other family. Christiaans et al (2010) also report at least one family with HCM and this variant (unclear if more than one or how many affected). Ehlermann et al (2008) also reported the variant in two family members with HCM. The London group included two patients with this variant in a study of cardiac phenotype in "G+LVH-" cases from their cohort (Captur et al 2014). They did not note if a family member had HCM and the variant. The variant has also likely been seen in three additional cases. The nomenclature used in these publications differs, which may be due to a difference in the exon and intron numbering scheme. Niimura et al (1998) found “Int12ASA-2G” in two families, with a total 11 individuals who were genotype and phenotype positive. Richard et al (2003) identified “IVS12–2:a7308g” in one index patient. Bonne et al (1995) sequenced mRNA from affected family members with this variant and found evidence of aberrant splicing with two mRNAs of abnormal length. One of these included a shift in frame and a resulting premature stop codon. Many other splice variants in MYBPC3 have been implicated in HCM: IVS2-1G>A, IVS6-2A>C, IVS7+1G>A, IVS8+1G>A, IVS8+5G>A, IVS12-2A>G, IVS16-1G>A, IVS15-13G>A, IVS14-2A>G, IVS18+2T>C, IVS20-2A>G, IVS21-2A>G, IVS22+2T>G, IVS22+1G>A, IVS23-2delA, IVS24+1G>A, IVS24+1G>T, IVS24-26A>G, IVS24-2A>G, IVS27+1G>A, IVS27+1delGT, IVS27-3C>G, IVS28+1G>A, IVS32+1G>A, IVS33+1G>A (see http://cardiogenomics.med.harvard.edu/project-detail?project_id=230 for list and references). In total the variant has not been seen in 6800 laboratory controls, published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of August 25th, 2014). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of August 25th,2014). The variant was not observed in the following laboratory and published control samples: 200 laboratory controls (GeneDx), 100 published controls (Boone et al 1995).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000609977 SCV000733058 pathogenic Hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000158322 SCV001923765 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000158322 SCV001959621 pathogenic not provided no assertion criteria provided clinical testing
deCODE genetics, Amgen RCV000609977 SCV004022233 pathogenic Hypertrophic cardiomyopathy 4 2023-07-21 no assertion criteria provided research The variant NM_000256.3:c.927-2A>G (chr11:47346372) in MYBPC3 was detected in 218 heterozygotes out of 58K WGS Icelanders (MAF= 0,188%). Following imputation in a set of 166K Icelanders (561 imputed heterozygotes) we observed an association with cardiomyopathy using 1974 cases and 365360 controls (OR= 48.62, P= 3.25e-170), heart failure using 20765 cases and 367806 controls (OR= 3.68, P= 1.27e-22), atrial fibrillation and flutter using 20168 cases and 351419 controls (OR= 2.73, P= 8.47e-12) and sudden cardiac death using 4784 cases and 358521 controls (OR= 1.93, P= 5.10e-03). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic.

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