Submissions for variant NM_004415.4(DSP):c.6452G>A (p.Arg2151Gln)

gnomAD frequency: 0.00005  dbSNP: rs367759510

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000419283	SCV000512885	uncertain significance	not provided	2016-12-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSP gene. The R2151Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency 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. Additionally, R2151Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Lastly, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000802736	SCV000942579	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-06-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188897	SCV001356071	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2151 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251180 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.
Phosphorus, Inc.	RCV001823728	SCV002073449	uncertain significance	not specified	2022-01-14	criteria provided, single submitter	clinical testing	This missense variant results in an amino acid substitution of Arginine with Glutamine at codon 2151 of the DSP gene (transcript: NM_004415.2). This variant has an entry in ClinVar (377813) NM_004415.4(DSP):c.6452G>A (p.Arg2151Gln). This variant occurred in gnomAD with a total MAF of 0 0.0012% and once with the highest MAF of 0.0058% in the East Asian population. This position is conserved. In silico functional algorithms predict this variant to be probably damaging (PolyPhen) and deleterious (SIFT). However, no functional studies were performed to confirm either of those predictions. The variant has not occurred in the literature in association with the disease. Considering that this is a rare variant and the available evidence is not enough to ascertain its role in disease, it has been classified as Variant of Uncertain Significance.
Ambry Genetics	RCV002365468	SCV002657467	uncertain significance	Cardiovascular phenotype	2022-06-07	criteria provided, single submitter	clinical testing	The p.R2151Q variant (also known as c.6452G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 6452. The arginine at codon 2151 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002480284	SCV002781050	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-07-22	criteria provided, single submitter	clinical testing