Submissions for variant NM_004415.4(DSP):c.3277G>A (p.Ala1093Thr)

gnomAD frequency: 0.00001  dbSNP: rs1185986064

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498000	SCV000589724	uncertain significance	not provided	2018-10-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSP gene. The A1093T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The A1093T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000815614	SCV000956075	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1093 of the DSP protein (p.Ala1093Thr). This variant is not present in population databases (gnomAD no frequency). 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: 432051). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001184491	SCV001350470	uncertain significance	Cardiomyopathy	2022-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1093 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.
Ambry Genetics	RCV002323862	SCV002611080	uncertain significance	Cardiovascular phenotype	2019-11-12	criteria provided, single submitter	clinical testing	The p.A1093T variant (also known as c.3277G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 3277. The alanine at codon 1093 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.