Submissions for variant NM_004415.4(DSP):c.423-1G>T

dbSNP: rs1304410089

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497916	SCV000590153	pathogenic	not provided	2017-05-30	criteria provided, single submitter	clinical testing	Although the c.423-1 G>T variant has not been reported as a pathogenic or benign to our knowledge, functional studies show that a variant at the same nucleotide position, c.423-1 G>A, leads to aberrant spliced mRNA products that lead to a truncated protein (Bauce et al., 2005). Additionally, this nucleotide substitution occurs at a position that is conserved across species. The c.423-1 G>T variant destroys the canonical splice acceptor site in intron 3 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the DSP gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.423-1 G>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics	RCV000621858	SCV000735571	pathogenic	Cardiovascular phenotype	2016-10-25	criteria provided, single submitter	clinical testing	The c.423-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 4 of the DSP gene. This alteration has not been reported in the literature to date; however, an alteration involving the same nucleotide position, c.423-1G>A, has been reported in a family with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and sudden death. The authors indicated RNA sequencing showed skipping of exon 4, which was predicted to result in a truncated or absent protein (Bauce B et al. Eur Heart J. 2005;26(16):1666-75). 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 pathogenic mutation.
Invitae	RCV001851377	SCV002280031	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2021-03-13	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. This variant has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 15941723). ClinVar contains an entry for this variant (Variation ID: 432430). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 3 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).