Submissions for variant NM_000256.3(MYBPC3):c.2905+1G>A

dbSNP: rs397515991

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195678	SCV000059187	pathogenic	Hypertrophic cardiomyopathy	2017-07-10	criteria provided, single submitter	clinical testing	The c.2905+1G>A variant in MYBPC3 has been reported in >10 individuals with HCM and segregated with disease in at least 3 affected members from two families (Ki mura 1997, Erdmann 2001, Walsh 2016, LMM unpublished data) and has also been rep orted in ClinVar (Variation ID 42666). It was absent from large population studi es. This variant occurs in the invariant region (+/- 1,2) of the splice consensu s sequence and has been shown to cause altered splicing in vitro and in vivo, le ading to an abnormal or absent protein (Erdmann 2001, Helms 2014). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, the c.2905+1G>A meets criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon presence in multiple affected indiv iduals, segregation and functional studies.
GeneDx	RCV000158196	SCV000208131	pathogenic	not provided	2022-07-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Messenger RNA functional studies demonstrated in-frame skipping of exon 27, which was hypothesized to result in loss of 56 highly conserved amino acids residues that are important for the incorporation of myosin-binding protein C into the A band (Erdmann et al., 2001); An additional functional study demonstrated in-frame skipping of exon 27 led to creation of a premature termination codon at the junction of exons 26 and 28, which resulted in mRNA instability (Helms et al., 2014); Canonical splice donor site variant in intron 27 expected to result in aberrant splicing; This variant is associated with the following publications: (PMID: 30550750, 33673806, 26582918, 8834242, 27620334, 30456444, 34542152, 23074333, 25525159, 9241277, 27483260, 27532257, 29875314, 21959974, 25611685, 23396983, 25351510, 24510615, 28916354, 12974739, 31737537, 31447099, 21302287, 11499719, 25031304)
Invitae	RCV000195678	SCV000253813	pathogenic	Hypertrophic cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 27 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. 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: 9241277, 11499719, 21302287, 21959974, 30550750). This variant is also known as IVS27 +1G>A. ClinVar contains an entry for this variant (Variation ID: 42666). Studies have shown that disruption of this splice site results in skipping of exon 27, but is expected to preserve the integrity of the reading-frame (PMID: 11499719, 25031304). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000035537	SCV000256156	uncertain significance	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619925	SCV000740088	pathogenic	Cardiovascular phenotype	2021-09-02	criteria provided, single submitter	clinical testing	The c.2905+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 27 of the MYBPC3 gene. This mutation, also referred to as IVS27+1G>A, has been detected numerous times in individuals with hypertrophic cardiomyopathy (HCM) and in HCM cohorts (Kimura A et al. Nat. Genet. 1997;16:379-82; Erdmann J et al. J. Am. Coll. Cardiol. 2001;38:322-30; Roncarati R et al. J. Cell. Physiol. 2011;226:2894-900; Bashyam MD et al. Mol. Cell. Biochem. 2012;360:373-82; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet Med. 2016;epub). Several RNA studies have demonstrated that this mutation causes the skipping of exon 27, creating a transcript with a premature stop codon at the exon 26-exon 28 intersection that undergoes nonsense-mediated decay (Erdmann J et al. J. Am. Coll. Cardiol. 2001;38:322-30; Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Monteiro da Rocha A et al. J. Mol. Cell. Cardiol. 2016;99:197-206). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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.
Blueprint Genetics	RCV000158196	SCV000927435	pathogenic	not provided	2017-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269119	SCV001448363	pathogenic	Primary familial hypertrophic cardiomyopathy	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2905+1G>A 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: Three predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Erdmann_2001). The variant was absent in 199606 control chromosomes. c.2905+1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Kimura_1997, Erdmann_2001, Erdmann_2003, Roncarati_2011, Lopes_2013, , Kapplinger_2014). These data indicate that the variant is very likely to be associated with disease. Seven 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000035537	SCV002521035	pathogenic	Hypertrophic cardiomyopathy 4	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042666). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Color Diagnostics, LLC DBA Color Health	RCV003531912	SCV004358657	pathogenic	Cardiomyopathy	2023-02-07	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 27 of the MYBPC3 gene. Functional RNA studies have shown that this variant causes in-frame skipping of exon 27, resulting in creation of a stop codon at the junction of exons 26 and 28 and a significant reduction of mutant mRNA transcript in heart tissue and cell lines from individuals carrying this variant (PMID: 11499719, 25031304, 27620334). This variant has been reported in at least 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 11499719, 21302287, 21959974, 23396983, 27532257). 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.
All of Us Research Program, National Institutes of Health	RCV000195678	SCV004814322	pathogenic	Hypertrophic cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 27 of the MYBPC3 gene. Functional RNA studies have shown that this variant causes in-frame skipping of exon 27, resulting in creation of a stop codon at the junction of exons 26 and 28 and a significant reduction of mutant mRNA transcript in heart tissue and cell lines from individuals carrying this variant (PMID: 11499719, 25031304, 27620334). This variant has been reported in at least 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 11499719, 21302287, 21959974, 23396983, 27532257). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158196	SCV000280252	likely pathogenic	not provided	2015-06-23	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 IVS27+1 G>A Based on the data reviewed below, we consider it very likely disease causing. Many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Harvard Sarcomere Protein Gene Mutation Database), and splice variants in MYBPC3 are a well-established cause of HCM. Of note, similarly-positioned donor splice site mutations in at least 7 other exons have been reported to cause HCM: IVS7+1G>A, IVS8+1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database). The G at this +1 consensus splice sequence site is completely conserved across vertebrate evolution. This specific variant has been previously seen in at least 3 unrelated families. Erdmann et al. reported IVS27+1 G>A in 2001 along with weak segregation data: The variant cosegregated with disease in 2 affected members of an HCM family, an affected mother and her affected son (it was also present in an unaffected daughter). An analysis of the mRNA in HCM patients’ lymphocytes confirmed the existence of abnormal splice products; IVS27+1 G>A led to in-frame skipping of exon 27 and the loss of 56 highly conserved amino acid residues that the researchers claim are important for incorporating myosin-binding protein C into the A band. Erdmann et al. (2003) reported that the IVS27+1 G>A variant was not present in more than 50 presumably healthy controls recruited in Germany. The variant is not reported in the NHLBI Exome Sequencing Project data set (http://evs.gs.washington.edu/EVS/), nor is a +1 donor splice site variant reported for any exon of MYBPC3 as of December 28, 2011. IVS27+1 G>A is not present in dbSNP (www.ncbi.nlm.nih.gov/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.html). The 1000 Genomes samples from the Bushman population appear to contain some +1 G>A variants at other exons in the MYBPC3 gene, but this was not explored in depth.