ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.521G>T (p.Cys174Phe) (rs377507763)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181276 SCV000233565 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The C174F variant has been reported in one patient referred for DCM genetic testing (Walsh et al., 2017); however, additional clinical details and segregation information were not provided. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C174F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is only conserved in mammals. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000526423 SCV000641316 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 174 of the DSP protein (p.Cys174Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs377507763, ExAC 0.01%) but has not been reported in the literature in individuals with a DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199851). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on DSP function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000781333 SCV000919288 uncertain significance not specified 2019-06-17 criteria provided, single submitter clinical testing Variant summary: DSP c.521G>T (p.Cys174Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251302 control chromosomes (gnomAD). The observed variant frequency is approximately 6-folds over the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.521G>T has been reported in the literature in an individual with DCM, without strong evidence for causality (Walsh_2017). This report does not provide an unequivocal conclusion about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000181276 SCV001154625 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing

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