Submissions for variant NM_004415.4(DSP):c.2436+2T>C

gnomAD frequency: 0.00001  dbSNP: rs774514264

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420343	SCV000531013	likely pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	Identified in a patient with DCM in published literature, but familial segregation information and additional clinical information were not included (Horvat et al., 2019); Not observed at a 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: 31447099, 31589614, 31402444, 33684294, 33087929, 29892087)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000611197	SCV000713317	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-01-17	criteria provided, single submitter	clinical testing	The c.2436+2T>C variant in DSP has not been previously reported in the literatur e in individuals with cardiomyopathy, but has been reported by other clinical la boratories in ClinVar (Variation ID: 388661). It has also been identified in 1/6 6720 European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org/; dbSNP rs774514264). This variant occurs in the invarian t region (+/- 1,2) of the splice consensus sequence and is predicted to cause al tered splicing leading to an abnormal or absent protein, which is common among d isease causing DSP variants. In summary, although additional studies are require d to fully establish its clinical significance, the c.2436+2T>C variant is likel y pathogenic.
Invitae	RCV001058578	SCV001223161	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-04-14	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 388661). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 29892087). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 17 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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486838	SCV004240517	pathogenic	Cardiomyopathy	2023-03-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003486838	SCV004363333	likely pathogenic	Cardiomyopathy	2023-06-22	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 17 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 29892087), and in several individuals from population-based cohorts whose clinical information were limited (PMID: 31447099, 31589614, 33684294). This variant has been identified in 1/251420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.