Submissions for variant NM_001943.5(DSG2):c.164C>T (p.Pro55Leu)

gnomAD frequency: 0.00001  dbSNP: rs748684045

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001064738	SCV000408199	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000419716	SCV000529473	uncertain significance	not provided	2016-07-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSG2 gene. The P55L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P55L variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P55L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064738	SCV001229656	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 55 of the DSG2 protein (p.Pro55Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 326473). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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	RCV005402908	SCV006064782	uncertain significance	Cardiomyopathy	2025-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 55 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has been identified in 1/249492 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.