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

gnomAD frequency: 0.00001  dbSNP: rs768858918

Total submissions: 6

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)."
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685638	SCV000813125	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-12-07	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, which is part of the consensus splice site for this exon. This variant is present in population databases (rs768858918, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 199877). Variants that disrupt 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. 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.
Ambry Genetics	RCV002433788	SCV002750659	uncertain significance	Cardiovascular phenotype	2023-08-08	criteria provided, single submitter	clinical testing	The c.2985G>A variant (also known as p.E995E) is located in coding exon 21 of the DSP gene. This variant results from a G to A substitution at nucleotide position 2985. This nucleotide substitution does not change the glutamic acid at codon 995. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003532018	SCV004363348	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	This synonymous variant alters a conserved last nucleotide c.G of exon 21 in the DSP gene and is predicted to affect RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 4/251266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003996649	SCV004829495	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-08-15	criteria provided, single submitter	clinical testing	This synonymous variant alters a conserved last nucleotide c.G of exon 21 in the DSP gene and is predicted to affect RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 4/251266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004751347	SCV005357199	uncertain significance	DSP-related disorder	2024-05-28	no assertion criteria provided	clinical testing	The DSP c.2985G>A variant is not predicted to result in an amino acid change (p.=). This variant is located at the last nucleotide of the exon and is predicted to abolish the canonical splice donor site and create a cryptic splice donor site; however, it is uncertain if it would lead to a loss-of-function (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.