Submissions for variant NM_000256.3(MYBPC3):c.2067+1G>A

dbSNP: rs1444727212

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521997	SCV000616794	pathogenic	not provided	2019-06-28	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19149795, 30105547, 25525159, 16181148, 17263690, 20975235, 25281569)
Color Diagnostics, LLC DBA Color Health	RCV001188456	SCV001355515	pathogenic	Cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This variant disrupts intron 21 canonical splice donor site of the MYBPC3 gene. An RNA study has shown that this variant causes skipping of exon 21 and creates a premature translation stop codon in exon 22 (PMID: 16181148). This variant has been reported in almost 20 individuals affected with hypertrophic cardiomyopathy, including at least 15 Japanese individuals (PMID: 16181148, 17263690, 19149795, 20975235, 28420666, 30105547). 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. Based on available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227424	SCV001399783	pathogenic	Hypertrophic cardiomyopathy	2019-10-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed to segregate with hypertrophic cardiomyopathy in families and has been observed in individuals affected with this condition (PMID: 16181148, 20975235). ClinVar contains an entry for this variant (Variation ID: 449066). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 21 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
3billion	RCV001809465	SCV002058827	pathogenic	Hypertrophic cardiomyopathy 4	2022-01-03	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000449066). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002420305	SCV002724874	pathogenic	Cardiovascular phenotype	2024-01-24	criteria provided, single submitter	clinical testing	The c.2067+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 21 of the MYBPC3 gene. This alteration has been detected in multiple probands with hypertrophic cardiomyopathy (HCM), segregated with disease in families, and was reported to result in aberrant splicing resulting in skipping of exon 21 and a premature stop codon in exon 22 (Konno T et al. Clin Sci. 2006;110:125-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel 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.
Genetics and Molecular Pathology, SA Pathology	RCV001809465	SCV002761691	pathogenic	Hypertrophic cardiomyopathy 4	2022-05-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001227424	SCV004818116	pathogenic	Hypertrophic cardiomyopathy	2023-11-09	criteria provided, single submitter	clinical testing	The c.2067+1G>A variant of the MYBPC3 gene disrupts the splicing acceptor site in intron 21 and is expected to alter RNA splicing. This alteration has been detected in multiple individuals with hypertrophic cardiomyopathy (HCM) (PMID: 16181148, 17263690, 19149795, 20975235, 30105547). It has also been observed to segregate with disease in families and was reported to result in aberrant splicing resulting in skipping of exon 21 and a premature stop codon in exon 22 (PMID: 16181148). 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 absent in the general population by the gnomAD database. Based on these evidence, the c.2067+1G>A variant of the MYBPC3 gene is classified as pathogenic.