Submissions for variant NM_004415.4(DSP):c.2130+1G>A

dbSNP: rs727505115

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156570	SCV000206289	likely pathogenic	Primary dilated cardiomyopathy	2014-05-08	criteria provided, single submitter	clinical testing	The 2130+1G>A variant in DSP has not been previously reported in individuals wit h cardiomyopathy or in large population studies. This variant occurs in the inv ariant region (+/- 1,2) of the splice consensus sequence and is predicted to cau se altered splicing leading to an abnormal or absent protein. A similar variant (2130+1G>C) has been reported in 1 adult with biventricular dilation and PVCs an d segregated with disease in 3 affected relatives (Elliott 2010). In summary, al though additional studies are required to fully establish its clinical significa nce, the 2130+1G>A variant is likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390851	SCV004112035	likely pathogenic	DSP-related condition	2023-03-09	criteria provided, single submitter	clinical testing	The DSP c.2130+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with arrhythmogenic right ventricular cardiomyopathy (supplementary file 2 - van Lint et al. 2019. PubMed ID: 30847666). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in DSP are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003531990	SCV004363321	likely pathogenic	Cardiomyopathy	2023-08-21	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the DSP gene. Splice site prediction tools predict 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Another variant at the same position, c.2130+1G>C (also known as IVS15+1G>C), has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257) and in another individual affected with idiopathic dilated cardiomyopathy (PMID: 20716751). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV003764976	SCV004578925	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 of the DSP 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 DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with DSP-related conditions (PMID: 27532257, 30847666). ClinVar contains an entry for this variant (Variation ID: 179772). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Clinical Genetics, Academic Medical Center	RCV001699211	SCV001925872	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699211	SCV001951985	likely pathogenic	not provided		no assertion criteria provided	clinical testing