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

gnomAD frequency: 0.00001  dbSNP: rs774514264

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420343	SCV000531013	likely pathogenic	not provided	2025-01-07	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with DCM in published literature, but familial segregation information and additional clinical information were not included (PMID: 29892087); This variant is associated with the following publications: (PMID: 31447099, 31589614, 31402444, 33684294, 33087929, 36264615, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058578	SCV001223161	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-04-20	criteria provided, single submitter	clinical testing	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). 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 cardiomyopathy (PMID: 29892087, 36264615). ClinVar contains an entry for this variant (Variation ID: 388661). 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.
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.
All of Us Research Program, National Institutes of Health	RCV004000501	SCV004825188	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-01-08	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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004556786	SCV005045689	likely pathogenic	Arrhythmogenic right ventricular dysplasia 8	2022-08-23	criteria provided, single submitter	clinical testing	The c.2436+2T>C variant of the DSP gene impacts the splice donor site in intron 7. It is predicted to disrupt RNA splicing. Variants that disrupt the splice site typically lead to loss of protein function. Variants leading to loss of function in DSP have been shown to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant has been reported in individuals with or at risk for cardiomyopathy (PMID: 33684294, 29892087). The frequency of this variant in the general population database (gnomAD) is rare (1/25142). ClinVar contains an entry for this variant (Variation ID: 388661). Based on the available evidence, this variant is classified as likely pathogenic.
Ambry Genetics	RCV004992210	SCV005575848	uncertain significance	Cardiovascular phenotype	2024-10-09	criteria provided, single submitter	clinical testing	The c.2436+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 17 in the DSP gene. This variant has been reported in an individual in a dilated cardiomyopathy cohort, but clinical details were limited (Horvat C et al. Genet Med, 2019 Jan;21:133-143). 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. 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; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). Based on the available evidence, the clinical significance of this alteration remains unclear.