Submissions for variant NM_004415.4(DSP):c.4901G>A (p.Arg1634Gln)

gnomAD frequency: 0.00007  dbSNP: rs144106775

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766881	SCV000233620	uncertain significance	not provided	2022-06-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203117	SCV000257968	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-06-08	criteria provided, single submitter	clinical testing
Invitae	RCV000704467	SCV000833418	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181324	SCV000917308	uncertain significance	not specified	2017-12-26	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.4901G>A (p.Arg1634Gln) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 16/275676 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.00026 (8/30744). This frequency is about 26 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign, until more evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001181056	SCV001346121	uncertain significance	Cardiomyopathy	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1634 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 arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has been identified in 15/281318 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	RCV002336446	SCV002639616	uncertain significance	Cardiovascular phenotype	2023-06-26	criteria provided, single submitter	clinical testing	The p.R1634Q variant (also known as c.4901G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4901. The arginine at codon 1634 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases. (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is not well conserved in available 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000181324	SCV000280090	uncertain significance	not specified	2014-04-22	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we consider this a variant of unknown significance (VUS). Mutations in the DSP gene have been reported in patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC). This variant has not been reported previously in patients with cardiomyopathy, nor has it been reported as a benign polymorphism. This is a non-conservative amino acid change from a positively-charged arginine to a polar, uncharged glutamine. The arginine at codon 1634 is not conserved across species (it is an arginine in 8 out of 9 vertebrate species, and the default amino acid is glutamine in lamprey). In silico analysis with PolyPhen-2 predicts the variant to be “benign” with a score of 0.090. No nearby residues have been listed in HGMD in association with cardiomyopathy (HGMD professional version as of January 17, 2014). In total the variant has been seen in 2 out of ~6500 individuals from population datasets. It was found in 1 Caucasian individual and 1 African-American individual in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no variant at codon 1634 listed in 1000 Genomes (as of March 27, 2014).