Submissions for variant NM_004415.4(DSP):c.4648A>G (p.Thr1550Ala)

dbSNP: rs375917565

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483906	SCV000572968	uncertain significance	not provided	2017-02-06	criteria provided, single submitter	clinical testing	The T1550A variant of uncertain significance in the DSP gene has not been published as pathogenic or been reported as benign to our knowledge. T1550A is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1550A 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. Nevertheless, this substitution occurs at a position that is not conserved, where A1550 is the native residue in at least two species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function, and no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851247	SCV002177315	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2021-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with alanine at codon 1550 of the DSP protein (p.Thr1550Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC 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: 423291). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
All of Us Research Program, National Institutes of Health	RCV004003396	SCV004826136	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1550 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 DSP-related 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.