ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1597C>T (p.Pro533Ser) (rs146132083)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000155342 SCV000169821 benign not specified 2014-03-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155342 SCV000205028 uncertain significance not specified 2018-06-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Pro533Ser var iant in WFS1 has been reported in 1 individual with Wolfram Syndrome and 1 indiv idual with post-lingual mild sensorineural hearing loss, but a second variant in WFS1 was not identified in either case (Prince 2012, LMM data). This variant wa s identified in an unaffected parent, suggesting that it would not cause the dom inant form of disease. This variant has also been identified in 0.12% (82/67552) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadi nstitute.org; dbSNP rs146132083), though this frequency is not high enough to ru le out a pathogenic role. Computational prediction tools and conservation analys is suggest that the Pro533Ser variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Pro533Ser variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP c riteria applied: BS1_Supporting.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724541 SCV000232700 uncertain significance not provided 2018-07-03 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV000664090 SCV000787542 likely benign Monogenic diabetes 2018-01-12 criteria provided, single submitter research ACMG criteria: PP3 (10 predictors), BS2 ( 8 controls and 5 cases in T2DM), BP6 (GeneDx says benign), NOTE: Emory and Partners call it VUS, (previously reported in patient with optic atrophy, hearing loss, neurogenic bladder, but no diabetes), PMID 28432734)=likely benign
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724541 SCV000892392 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001151986 SCV001313178 uncertain significance Autosomal dominant nonsyndromic deafness 6 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001151987 SCV001313179 uncertain significance WFS1-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000724541 SCV001557511 uncertain significance not provided 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 533 of the WFS1 protein (p.Pro533Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs146132083, ExAC 0.1%). This variant has been observed in individual(s) with clinical features of autosomal recessive Wolfram syndrome (PMID: 26875006, 28432734, 31264968). ClinVar contains an entry for this variant (Variation ID: 137914). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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.

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