ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.400G>A (p.Ala134Thr)

gnomAD frequency: 0.00016  dbSNP: rs147724970
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000585599 SCV000252555 uncertain significance not provided 2022-09-07 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19292454, 20738327, 27617222)
CeGaT Center for Human Genetics Tuebingen RCV000585599 SCV000693143 uncertain significance not provided 2023-05-01 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000585599 SCV000859981 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826085 SCV000967580 uncertain significance not specified 2018-08-30 criteria provided, single submitter clinical testing The p.Ala134Thr variant in WFS1 has not been previously reported in individuals with hearing loss, Wolfram syndrome, or Wolfram like syndrome, but has been iden tified in 0.03% (26/101904) European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). This variant has also been reported in ClinVar (Variation ID 2154 10). Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, the clinical s ignificance of the p.Ala134Thr variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.
Illumina Laboratory Services, Illumina RCV001157024 SCV001318570 uncertain significance Autosomal dominant nonsyndromic hearing loss 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 Laboratory Services, Illumina RCV001157025 SCV001318571 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.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV001174386 SCV001337524 uncertain significance Monogenic diabetes 2018-05-18 criteria provided, single submitter research ACMG criteria: PP3 (7 predictors + Revel score 0.806; not using BP4 (2 predictors)); c.397G>A/Ala133Thr has been published in literature in association with WFS1 (PMID: 24890733) = VUS
Invitae RCV000585599 SCV002259183 uncertain significance not provided 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 134 of the WFS1 protein (p.Ala134Thr). This variant is present in population databases (rs147724970, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 215410). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects WFS1 function (PMID: 19292454). 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.
Fulgent Genetics, Fulgent Genetics RCV002485312 SCV002779674 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2022-04-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000585599 SCV001553709 uncertain significance not provided no assertion criteria provided clinical testing The WFS1 p.Ala134Thr variant was identified in 1/30 individuals with hearing loss (Lewis_2018_PMID: 30180840). The variant was identified in dbSNP (ID: rs147724970) and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics, GeneDx, Laboratory for Molecular Medicine, and CeGaT Praxis fuer). The variant was identified in control databases in 33 of 236124 chromosomes at a frequency of 0.0001398 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 6416 chromosomes (freq: 0.000312), European (non-Finnish) in 30 of 104428 chromosomes (freq: 0.000287) and African in 1 of 20912 chromosomes (freq: 0.000048), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Ala134 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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