ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2985G>A (p.Glu995=) (rs768858918)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181311 SCV000233604 likely pathogenic not provided 2014-07-16 criteria provided, single submitter clinical testing p.Glu995Glu (GAG>GAA): c.2985 G>A in exon 21 of the DSP gene (NM_004415.2). The c.2985 G>A variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The c.2985 G>A mutation results in a synonymous change of the residue E995 in the DSP gene, which alters the last nucleotide of exon 21, immediately 5' of the cannonical GT" splice donor site. In silico analysis predicts this mutation destroys the donor site at the exon 21/intron 21 junction in the DSP gene, which may lead to abnormal gene splicing. Furthermore, the c.2985 G>A mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in ARRHYTHMIA panel(s)."
Invitae RCV000685638 SCV000813125 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-03-29 criteria provided, single submitter clinical testing This sequence change affects codon 995 of the DSP mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DSP protein. This variant also falls at the last nucleotide of exon 21 of the DSP coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs768858918, ExAC 0.02%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199877). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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