Submissions for variant NM_000256.3(MYBPC3):c.906-36G>A

dbSNP: rs864622197

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205089	SCV000259662	pathogenic	Hypertrophic cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18337725, 31730716; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219660). Studies have shown that this variant results in creation of a de novo splice acceptor and introduces a premature termination codon (PMID: 18337725). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004909	SCV001164411	likely pathogenic	Hypertrophic cardiomyopathy 4	2018-12-03	criteria provided, single submitter	research	The heterozygous c.906-36G>A variant in MYBPC3 was identified by our study in one individual with familial hypertrophic cardiomyopathy. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the c.906-36G>A variant may impact protein function by creating an acceptor splice site and a 34 nucleotide insertion in the transcript, leading to a frameshift in Exon 10 and premature termination codon in Exon 12 (PMID: 18337725). However, these types of assays may not accurately represent biological function.This variant was absent from large population studies. This variant has been reported pathogenic and was reported to cosegregate with familial hypertrophic cardiomyopathy in one family in ClinVar (Variation ID: 219660) and was reported in the homozygous state in one unrelated individual with hypertrophic cardiomyopathy (PMID: 18337725). In summary, although additional studies are required to fully establish its clinical significance, the c.906-36G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PP1, PP3 (Richards 2015).
Color Diagnostics, LLC DBA Color Health	RCV001524823	SCV001734783	likely pathogenic	Cardiomyopathy	2020-05-01	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -36 position of intron 9 of the MYBPC3 gene. A RT-PCR study using cells from a carrier individual has shown that this variant creates a new splice acceptor site and causes the inclusion of 34 nucleotides of intron 9 into exon 10, leading to a frameshift in exon 10 and premature termination codon in exon 12 (PMID: 18337725). This mutant transcript is expected to result in an absent or non-functional protein product. This variant has been reported in up to seven unrelated individuals affected with hypertrophic cardiomyopathy, as well as in a mother and a daughter from one family affected with hypertrophic cardiomyopathy (PMID: 18337725, 31730716; Clinvar variation ID: 219660; communication with an external laboratory). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001778792	SCV002015617	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Non-canonical splice site variant demonstrated to result in loss-of-function; published functional mRNA studies demonstrate that this variant creates a de novo splice acceptor site in intron 9 and leads to abnormal gene splicing which results in the inclusion of an additional 34 nucleotides of intron 9 into the MYBPC3 mRNA (Frank-Hansen et al., 2008); Reported in ClinVar as pathogenic and noted to segregate with disease in a family by another clinical laboratory (ClinVar Variant ID 219660; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31730716, 29998127, 12974739, 18337725, 30297972, 22267749, 32396390, 27535533)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001524823	SCV002042239	pathogenic	Cardiomyopathy	2022-10-27	criteria provided, single submitter	clinical testing
3billion	RCV001004909	SCV002058237	likely pathogenic	Hypertrophic cardiomyopathy 4	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 29355681, PS2_S). In silico prediction tools predicted that this variant influenced pre-mRNA splicing, resulting in aberrant splicing (SPLICEAI: 0.91, PP3_P). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000219660, 3billion dataset). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002372195	SCV002687690	pathogenic	Cardiovascular phenotype	2021-07-07	criteria provided, single submitter	clinical testing	The c.906-36G>A intronic pathogenic mutation results from a G to A substitution 36 nucleotides upstream from coding exon 10 in the MYBPC3 gene. This alteration (also referred to as IVS9-36G>A) has been reported in multiple individuals in hypertrophic cardiomyopathy (HCM) cohorts, and RNA studies revealed aberrant splicing resulting in premature protein truncation (Erdmann J et al. Clin Genet, 2003 Oct;64:339-49; Frank-Hansen R et al. Eur. J. Hum. Genet., 2008 Sep;16:1062-9; Salman OF et al. Front Cardiovasc Med, 2018 Jun;5:77; Janin A et al. Hum Mutat, 2020 02;41:465-475; Lopes LR et al. Circ Genom Precis Med, 2020 06;13:e002905, Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000205089	SCV004848323	likely pathogenic	Hypertrophic cardiomyopathy	2020-05-01	criteria provided, single submitter	clinical testing	The c.906-36G>A variant in MYBPC3 has been reported in at least 6 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 1 affected individual (Frank-Hansen 2008 PMID:18337725, Janin 2020 PMID: 31730716 , ClinVar: SCV000259662). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 219660). This variant is located in the 3' splice region. Computational tools and in vitro studies with patient leukocytes predict a splicing impact, though this information is not predictive enough to determine pathogenicity (Frank-Hansen 2008 PMID:18337725). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PS4_Moderate.