Submissions for variant NM_000256.3(MYBPC3):c.2737+1G>A

dbSNP: rs727504314

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, University of Leuven	RCV000768476	SCV000886764	pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000768476	SCV001577442	pathogenic	Hypertrophic cardiomyopathy	2024-02-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 26 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: 25611685, 31513939, 31747981). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 619256). 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.
All of Us Research Program, National Institutes of Health	RCV000768476	SCV004842559	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-15	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 21959974, 33495596). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Color Diagnostics, LLC DBA Color Health	RCV005401599	SCV006061477	likely pathogenic	Cardiomyopathy	2024-03-25	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 26 of the MYBPC3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 25040344, 31513939, 33495596, 33495597). It has been shown that this variant segregates with disease in three affected individuals from one family (PMID: 25040344). 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 the available evidence, this variant is classified as Likely Pathogenic.
Clinical Genetics, Academic Medical Center	RCV001700455	SCV001923708	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001700455	SCV001959675	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001700455	SCV001972747	pathogenic	not provided		no assertion criteria provided	clinical testing