Submissions for variant NM_000256.3(MYBPC3):c.26-2A>G

gnomAD frequency: 0.00002  dbSNP: rs376395543

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000470636	SCV000059162	pathogenic	Hypertrophic cardiomyopathy	2019-08-29	criteria provided, single submitter	clinical testing	The c.26-2A>G variant in MYBPC3 has been reported in >10 individuals with HCM, segregated with disease in 4 affected relatives from 3 families, including 1 obligate carrier (Van Driest 2004, Ehlermann 2008, Waldmuller 2011, Page 2012, Kapplinger 2014, LMM unpublished data). It has also been reported in ClinVar (Variation ID 42644), in 7/114350 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376395543), and in 2 unaffected adults (Natarajan 2016, LMM unpublished data). For diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Finally, this variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence, and the variant is predicted to damage the canonical splice site. Heterozygous splice variants in MYBPC3 are prevalent in cases of HCM. However, an alternate splice site is predicted to occur 6 bps downstream, and, if used, would lead to an in-frame deletion of 2 amino acids, though these computational tools are not predictive enough to suggest this alternative splice site would be use in vivo. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon predicted impact to the protein, presence in affected individuals and segregation studies. The ACMG/AMP Criteria applied: PS4; PM4; PP1_Supporting; PM2_Supporting.
GeneDx	RCV000158174	SCV000208109	pathogenic	not provided	2023-04-12	criteria provided, single submitter	clinical testing	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.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27532257, 25637381, 18957093, 24510615, 29029073, 34542152, 15519027, 22267749, 21750094, 27831900, 23674513, 31447099, 34570182, 33673806, 32686758, 33258288, 34135346, 33087929, 34691145, 35537032)
Invitae	RCV000470636	SCV000546423	pathogenic	Hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 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 present in population databases (rs376395543, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 22267749, 23674513, 24510615, 27532257). ClinVar contains an entry for this variant (Variation ID: 42644). 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	RCV000621287	SCV000739931	pathogenic	Cardiovascular phenotype	2019-09-20	criteria provided, single submitter	clinical testing	The c.26-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the MYBPC3 gene. This mutation has been previously reported in individuals with hypertrophic cardiomyopathy (HCM) and left ventricular non-compaction (LVNC) (Page SP et al. Circ Cardiovasc Genet. 2012;5(2):156-66; Ehlermann P et al. BMC Med Genet. 2008;9:95; Van Driest SL et al. J Am Coll Cardiol. 2004;44(9):1903-10; Sedaghat-Hamedani F et al. Eur. Heart J., 2017 Dec;38:3449-3460; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000656561	SCV000778606	pathogenic	Hypertrophic cardiomyopathy 4	2018-05-08	criteria provided, single submitter	research
Blueprint Genetics	RCV000158174	SCV000927619	pathogenic	not provided	2018-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176811	SCV001340870	pathogenic	Cardiomyopathy	2023-03-27	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 1 splice acceptor site of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 21750094, 22267749, 23674513, 24510615, 27532257, 27831900) and has been shown to segregate with disease in 4 individuals from 2 families (communication with en external laboratory; ClinVar SCV000059162.6). This variant has been identified in 7/255378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000656561	SCV001366311	pathogenic	Hypertrophic cardiomyopathy 4	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000656561	SCV001429300	pathogenic	Hypertrophic cardiomyopathy 4	2019-05-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001255329	SCV001431715	pathogenic	Intellectual disability	2020-08-03	criteria provided, single submitter	clinical testing	The variant c.26-2A>G, p.? was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was unknown.The variants does not (fully) explain the NDD in this individual
DASA	RCV001849291	SCV002107113	pathogenic	MYBPC3-Related Disorders	2022-03-05	criteria provided, single submitter	clinical testing	The c.26-2A>G variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42644; PMID: 15519027; PMID: 18957093; PMID: 23674513; PMID: 24510615; PMID: 22267749; PMID: 27532257) - PS4. The variant is present at low allele frequencies population databases (rs376395543 – gnomAD 0.0002741%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 18957093; 22267749) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000158174	SCV002502927	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002280095	SCV002568302	likely pathogenic	Left ventricular noncompaction 10	2022-04-26	criteria provided, single submitter	clinical testing	PVS1, PM2
MGZ Medical Genetics Center	RCV002280095	SCV002580769	likely pathogenic	Left ventricular noncompaction 10	2022-01-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496530	SCV002808696	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2022-03-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001176811	SCV003837608	pathogenic	Cardiomyopathy	2021-09-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000158174	SCV003916715	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MYBPC3: PVS1, PM2
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002496530	SCV003920227	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-03-30	criteria provided, single submitter	clinical testing	MYBPC3 NM_000256.3 exon 2 c.26-2A>G: This variant has been reported in the literature in several individuals with HCM or LVNC, segregating with disease in multiple affected family members within at least two families (Van Driest 2004 PMID:15519027, Ehlermann 2008 PMID:18957093, Page 2012 PMID:22267749, Sedaghat-Hamedani 2017 PMID:29029073, Walsh 2017 PMID:27532257). This variant is present in 0.005% (6/115748) of European alleles in the Genome Aggregation Database http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, reduced penetrance, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:42644). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Marston 2009 PMID:19574547). In summary, this variant is classified as pathogenic based on the data above (segregation studies, impact to protein etc.)
New York Genome Center	RCV002496530	SCV003925325	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2022-09-16	criteria provided, single submitter	clinical testing	The c.26-2A>G variant identified in the MYBPC3 gene has been reported in ClinVar as Pathogenic by multiple submitters (VarID:42644) and has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature [PMID: 15519027, 18957093, 27532257, 33673806,others.] The c.26-2A>G variant is observed in 10 alleles (~0.002% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.26-2A>G variant in MYBPC3 is located inthe canonical splice acceptor site preceding exon 2 of this 34-exon gene, and is presumed to affect mRNA splicing which might result in exon skipping or full/partial intron retention. Based on available evidence this c.26-2A>G variant identified in MYBPC3 is classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000158174	SCV004026045	pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing	PP1_STR, PS4, PVS1_MOD, PM2_SUP
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000656561	SCV004045794	pathogenic	Hypertrophic cardiomyopathy 4	2022-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421945	SCV004116699	pathogenic	MYBPC3-related condition	2023-08-14	criteria provided, single submitter	clinical testing	The MYBPC3 c.26-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in multiple patients with hypertrophic cardiomyopathy (Ehlermann et al. 2008. PubMed ID: 18957093; Witjas-Paalberends et al. 2013. PubMed ID: 23674513; Kapplinger et al. 2014. PubMed ID: 24510615). This variant is reported in 0.0052% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Variants that disrupt the consensus splice acceptor site in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic.
CSER _CC_NCGL, University of Washington	RCV000035512	SCV000190375	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000158174	SCV001920498	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000158174	SCV001927887	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158174	SCV001960078	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000158174	SCV001962828	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158174	SCV001966961	pathogenic	not provided		no assertion criteria provided	clinical testing