Submissions for variant NM_004415.4(DSP):c.616G>A (p.Ala206Thr)

dbSNP: rs794728109

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181277	SCV000233566	uncertain significance	not provided	2013-08-13	criteria provided, single submitter	clinical testing	p.Ala206Thr (GCC>ACC): c.616 G>A in exon 5 of the DSP gene (NM_004415.2). The Ala206Thr variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala206Thr results in a non-conservative amino acid substitution of a non-polar Alanine with a polar Threonine at a position that is not well conserved across species. In silico analysis predicts Ala206Thr is benign to the protein structure/function. No mutations in nearby residues have been reported in association with ARVC, indicating this region of the protein may be tolerant of change. Nevertheless, the Ala206Thr variant 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. With the clinical and molecular information available at this time, we cannot definitively determine if Ala206Thr is a disease-causing mutation or rare benign variant. The variant is found in ARVC panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553576	SCV001774476	uncertain significance	not specified	2021-07-27	criteria provided, single submitter	clinical testing	Variant summary: DSP c.616G>A (p.Ala206Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251340 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.616G>A has been reported in the literature in at least one individual with sudden death and causes of death could not be determined at autopsy (Sato_2015). This report does not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV002515307	SCV003514327	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-04	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 206 of the DSP protein (p.Ala206Thr). This variant is present in population databases (rs794728109, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 25693453). ClinVar contains an entry for this variant (Variation ID: 199852). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine 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.
Color Diagnostics, LLC DBA Color Health	RCV003532017	SCV004363274	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 206 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 been reported in an individual affected with sudden unexpected death (PMID: 25693453). This variant has been identified in 1/251340 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.