Submissions for variant NM_000256.3(MYBPC3):c.1928-2A>G

dbSNP: rs397515937

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000229899	SCV000059101	pathogenic	Hypertrophic cardiomyopathy	2019-08-14	criteria provided, single submitter	clinical testing	The c.1928-2A>G variant in MYBPC3 has been identified in >40 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in >20 affected relatives across several families (Bonne 1995, Charron 1998, Erdmann 2001, Richard 2003, Fokstuen 2008, Millat 2010, Teirlinck 2012, Valente 2013, Kapplinger 2014, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID:42585) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown to lead to aberrant splicing and subsequently a premature stop codon at position 661 (Bonne 1995, Flavigny 1999, Erdmann 2001). Please note that alternate nomenclature was used in some studies (Charron 1998: SAS int20; Richard 2003: IVS21-2A>G; Erdmann 2001: IVS20-2A>G). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PS3.
GeneDx	RCV000158133	SCV000208068	pathogenic	not provided	2021-12-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; mRNA functional studies have demonstrated this variant leads to aberrant gene splicing and the introduction of a premature stop codon (Bonne et al., 1995; Erdmann et al., 2001; Helms et al., 2014); Multiple other splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (HGMD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42585; ClinVar); This variant is associated with the following publications: (PMID: 25031304, 20439259, 10610770, 28597742, 20624503, 24865491, 12707239, 9503187, 18409188, 23140321, 23348723, 25525159, 25611685, 23690394, 26743238, 26914223, 27532257, 28822653, 28369730, 24510615, 28790153, 25351510, 30128729, 31006259, 30550750, 31447099, 27688314, 31513939, 11499719, 7493026, 31737537, 33954932)
Invitae	RCV000229899	SCV000284218	pathogenic	Hypertrophic cardiomyopathy	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 20 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 individual(s) with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 12707239, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615). ClinVar contains an entry for this variant (Variation ID: 42585). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 10610770, 11499719, 25031304). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000009136	SCV000299246	pathogenic	Hypertrophic cardiomyopathy 4	2016-02-09	criteria provided, single submitter	clinical testing	This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with cardiomyopathy. The c.1928-2 A>G variant affects the canonical splice acceptor site of intron 20 and leads to aberrant gene splicing and the introduction of a premature stop codon (PMID: 11499719; PMID: 7493026; PMID: 25031304).
Ambry Genetics	RCV000250981	SCV000320293	pathogenic	Cardiovascular phenotype	2021-06-14	criteria provided, single submitter	clinical testing	The c.1928-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 21 in the MYBPC3 gene. This alteration was first reported in two large French kindreds with hypertrophic cardiomyopathy (HCM) (Bonne G et al. Nat Genet. 1995;11(4):438-40), and has since been reported in multiple unrelated individuals and families with HCM (Charron P et al. Eur Heart J. 1998;19(1):139-45 (reported as SAS int20); Richard P et al. Circulation. 2003;107(17):2227-32 (reported as IVS21-2A>G); Teirlinck CH et al. BMC Med Genet. 2012;3:105 (reported as IVS202A>G); Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61). This alteration has been shown to lead to abnormal splicing resulting in aberrant protein product (Bonne G et al. Nat Genet. 1995;11(4):438-40; Erdmann J et al. J Am Coll Cardiol. 2001;38(2):322-30). 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.
Fulgent Genetics, Fulgent Genetics	RCV000515302	SCV000611208	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2017-05-18	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000229899	SCV000886756	pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000009136	SCV000897968	pathogenic	Hypertrophic cardiomyopathy 4	2018-07-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779063	SCV000915529	pathogenic	MYBPC3-Related Disorders	2018-08-14	criteria provided, single submitter	clinical testing	The MYBPC3 c.1928-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1928-2A>G variant has not been observed in individuals with either autosomal dominant dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy. Across a selection of the available literature, the c.1928-2A>G variant has been identified in a heterozygous state in 28 families in which it was found in 82 individuals affected with hypertrophic cardiomyopathy, of whom up to 35 individuals are related, in five individuals with an unknown diagnosis or discrete signs of disease, and in six healthy carriers (Bonne et al. 1995; Charron et al. 1998; Erdmann et al. 2001; Richard et al. 2003; Teirlinck et al. 2012). The c.1928-2A>G variant was shown to segregate with disease in two four-generation French families and in a further 13 families of European origin (Bonne et al. 1995; Richard et al. 2003). One of the studies calculated disease penetrance to be 69% and described the variant as being associated with a mild ventricular hypertrophy (Charron et al. 1998). The c.1928-2A>G variant was absent from 600 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Analysis of MYBPC3 mRNA from patient lymphoblastoid cell lines showed that the c.1928-2A>G variant results in aberrant splicing, causing the skipping of exon 21 and a frameshift with the introduction of a premature stop codon after amino acid residue 661 (Bonne et al. 1995). Expression of the c.1928-2A>G variant in COS-7 cells revealed accumulation to a level similar to wild type, while in fetal rat cardiomyocytes, the variant accumulated to a level that was approximately two-thirds of wild type. Eleven percent of fetal rat cardiomyocyte cells expressing the variant localized correctly in double stripes in the A-band of the sarcomere, but in a more diffuse pattern compared to wild type (Flavigny et al. 1999). Based on the collective evidence and due to the potential impact of splice acceptor variants, the c.1928-2A>G variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000157326	SCV000987541	pathogenic	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177884	SCV001342181	pathogenic	Cardiomyopathy	2023-03-08	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 20 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that this variant causes aberrant splicing and is expected to result in an absent or disrupted protein product (PMID: 11499719, 25031304). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615, 28615295). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000158133	SCV001447265	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177884	SCV002042151	pathogenic	Cardiomyopathy	2022-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000158133	SCV002821623	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	MYBPC3: PVS1, PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000157326	SCV004803668	pathogenic	Primary familial hypertrophic cardiomyopathy	2024-01-23	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1928-2A>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. Publications report experimental evidence that this variant affects mRNA splicing (Erdmann_2001, Bonne_1995). The variant was absent in 248758 control chromosomes. c.1928-2A>G has been reported in the literature in numerous individuals and families affected with Hypertrophic Cardiomyopathy (ie. Erdmann_2001, Bonne_1995, Fokstuen_MYH7_2008. ClinVar contains an entry for this variant (Variation ID: 42585). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000009136	SCV000029353	pathogenic	Hypertrophic cardiomyopathy 4	1995-12-01	no assertion criteria provided	literature only
Blueprint Genetics	RCV000157326	SCV000207061	pathogenic	Primary familial hypertrophic cardiomyopathy	2014-10-07	no assertion criteria provided	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000229899	SCV001430861	pathogenic	Hypertrophic cardiomyopathy	2019-12-11	no assertion criteria provided	research	The MYBPC3 c.1928-2A>G variant has been identified in numerous HCM probands and has been shown to segregate with disease across several reported families (see references). This variant occurs at the canonical acceptor splice site of intron 20 and leads to aberrant splicing and subsequently a premature stop codon (Bonne G., et al 1995; Flavigny J., et al 1999; Erdmann J., et al 2001; Helms AS, et al., 2010). This variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in 9 HCM probands. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in more than 15 HCM probands (PS4), segregated in multiple families (PP1_Strong) and is rare in the general population (PM2), therefore we classify MYBPC3 c.1928A>G as 'Pathogenic'.