Submissions for variant NM_000256.3(MYBPC3):c.2149-1G>A

dbSNP: rs727504334

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465441	SCV000546468	pathogenic	Hypertrophic cardiomyopathy	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 22 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 individuals with hypertrophic cardiomyopathy (PMID: 23782526). ClinVar contains an entry for this variant (Variation ID: 177814). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506011	SCV000604328	pathogenic	not specified	2016-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000786163	SCV001831981	pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 30393631, 23782526, 37652022, 36129056, 34588271)
Revvity Omics, Revvity	RCV000786163	SCV002017656	pathogenic	not provided	2021-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281967	SCV002570549	pathogenic	Primary familial hypertrophic cardiomyopathy	2022-07-22	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2149-1G>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: Four predict the variant abolishes a 3 acceptor site. Experimental evidence supports these predictions indicating that this variant affects mRNA splicing (Mendez_2021). The variant was absent in 237380 control chromosomes (gnomAD). c.2149-1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Nunez_2013, Restrepo-Cordoba_2017, Mendez_2021). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002426737	SCV002730417	pathogenic	Cardiovascular phenotype	2021-12-18	criteria provided, single submitter	clinical testing	The c.2149-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 23 of the MYBPC3 gene. This alteration was first reported in a hypertrophic cardiomyopathy (HCM) cohort (Núñez L et al. Circ. J., 2013 Jun;77:2358-65) and has also been reported in another HCM clinical genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;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.
All of Us Research Program, National Institutes of Health	RCV000465441	SCV004839079	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 22 of the MYBPC3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Functional RNA studies have shown that this variant produces a mutant transcript that causes retention of intron 22, creating a frameshift and premature translation stop signal and expected to result in an absent or non-functional protein product (PMID: 34588271). This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 28771489, 32841044, 34588271). It has been shown that this variant segregates with disease in multiple affected individuals across 8 unrelated families (PMID: 34588271). 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.
Color Diagnostics, LLC DBA Color Health	RCV005402855	SCV006064835	pathogenic	Cardiomyopathy	2023-11-09	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 22 of the MYBPC3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Functional RNA studies have shown that this variant produces a mutant transcript that causes retention of intron 22, creating a frameshift and premature translation stop signal and expected to result in an absent or non-functional protein product (PMID: 34588271). This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 28771489, 32841044, 34588271). It has been shown that this variant segregates with disease in multiple affected individuals across 8 unrelated families (PMID: 34588271). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000465441	SCV000204115	pathogenic	Hypertrophic cardiomyopathy	2013-03-04	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786163	SCV000924854	pathogenic	not provided	2016-10-14	no assertion criteria provided	provider interpretation	c.2149-1G>A (Splice acceptor IVS 22-1G>A) in the MYBPC3 gene (NM_000256.3) We have seen this variant in a person with HCM. Testing was performed by Invitae. The variant type is a well established mechanism of disease in this gene and we consider this variant to be very likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been seen in at least 2 patients with HCM (not including this patient), representing weak case data. No segregation data is available. One LMM HCM patient is listed in the cardiodb site. Another HCM patient was reported in a Spanish cohort by Nunez, et al.,2013. Per the Invitae report, "This sequence change affects an acceptor splice site in intron 22 of the MYBPC3 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product." There is no variation at genomic position (11-47360231-G-A) listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 10/14/2016). The mean coverage at that site in ExAC is ~22x, median is ~19x, and >90% of people have 10x coverage.