ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4901G>A (p.Arg1634Gln) (rs144106775)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766881 SCV000233620 uncertain significance not provided 2014-03-20 criteria provided, single submitter clinical testing p.Arg1634Gln (CGG>CAG): c.4901 G>A in exon 23 of the DSP gene (NM_004415.2). The R1634Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1634Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R1634Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved across species. Futhermore in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Division of Genomic Diagnostics,The 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 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1634 of the DSP protein (p.Arg1634Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs144106775, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199887). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America 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.
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).

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