Submissions for variant NM_004415.4(DSP):c.596G>A (p.Arg199Lys)

gnomAD frequency: 0.00004  dbSNP: rs143648545

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615030	SCV000710899	uncertain significance	not specified	2017-03-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg199Lys var iant in DSP has not been previously reported in individuals with cardiomyopathy, but has been identified in 3/10388 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143648545). Arginine (Arg) at position 199 is not conserved in evolutionarily distant species, with > 20 species carrying a lysine (Lys) at this position, raising the possibility tha t a change at this position may be tolerated. Additional computational predictio n tools suggest that the p.Arg199Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg199Lys variant is uncertain, its pr esence in non-mammals suggests that it is more likely to be benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222968	SCV001395094	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-05-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 504526). This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is present in population databases (rs143648545, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 199 of the DSP protein (p.Arg199Lys).
Ambry Genetics	RCV002358667	SCV002658619	uncertain significance	Cardiovascular phenotype	2024-07-17	criteria provided, single submitter	clinical testing	The p.R199K variant (also known as c.596G>A), located in coding exon 4 of the DSP gene, results from a G to A substitution at nucleotide position 596. The arginine at codon 199 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other 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.
Color Diagnostics, LLC DBA Color Health	RCV003532184	SCV004363272	uncertain significance	Cardiomyopathy	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 199 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 been identified in 4/281652 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.
All of Us Research Program, National Institutes of Health	RCV004002474	SCV004824394	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 199 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 been identified in 4/281652 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.