Submissions for variant NM_004415.4(DSP):c.6442G>A (p.Ala2148Thr)

gnomAD frequency: 0.00004  dbSNP: rs144539278

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219958	SCV000271740	uncertain significance	not specified	2015-10-15	criteria provided, single submitter	clinical testing	The p.Ala2148Thr variant in DSP has not been previously reported in patients wit h cardiomyopathy but has been identified in 1/16484 of South Asian chromosomes a nd 1/10288 African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; rs144539278). Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala2148Thr variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071095	SCV001236382	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-07-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179802	SCV001344583	uncertain significance	Cardiomyopathy	2023-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2148 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the DSP gene (PMID: 31319917), in an individual affected with an unspecified cardiomyopathy with clinical limited details (PMID: 37477868), and in an individual affected with alcoholic cardiomyopathy (PMID: 29773157). This variant has been identified in 6/282610 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.
Ambry Genetics	RCV003362730	SCV004057614	uncertain significance	Cardiovascular phenotype	2023-09-14	criteria provided, single submitter	clinical testing	The p.A2148T variant (also known as c.6442G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 6442. The alanine at codon 2148 is replaced by threonine, an amino acid with similar properties. This variant has been detected in individuals from unspecified cardiomyopathy and alcohol-induced cardiomyopathy cohorts and co-occurred with a DSP nonsense mutation in a proband with arrhythmogenic right ventricular cardiomyopathy (Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; DeWitt ES et al. J Am Coll Cardiol, 2019 Jul;74:346-358; Akinrinade O et al. J Cardiovasc Transl Res, 2023 Jul). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003997736	SCV004814263	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2148 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the DSP gene (PMID: 31319917), in an individual affected with an unspecified cardiomyopathy with clinical limited details (PMID: 37477868), and in an individual affected with alcoholic cardiomyopathy (PMID: 29773157). This variant has been identified in 6/282610 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.
Breakthrough Genomics, Breakthrough Genomics	RCV001729464	SCV005188790	uncertain significance	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001729464	SCV001978569	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001729464	SCV001979540	uncertain significance	not provided		no assertion criteria provided	clinical testing