Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genomic Diagnostic Laboratory, |
RCV000238677 | SCV000297198 | uncertain significance | not specified | 2015-10-16 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000238677 | SCV000711244 | uncertain significance | not specified | 2017-12-05 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The p.Ala57Thr vari ant in WFS1 has not been previously reported in individuals with hearing loss. T his variant has been identified in 2/8708 African chromosomes by the Genome Aggr egation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs372783392) a nd has been reported in ClinVar (Variation ID: 252656) as a variant of uncertain significance in an individual with unspecified clinical status. Although this v ariant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The Alanine (Ala) at position 57 is not conserve d in mammals, and 2 mammals carry a Threonine (Thr) despite high nearby amino ac id conservation, raising the possibility that this change at this position may b e tolerated. Additional computational prediction tools suggest that the p.Ala57T hr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance o f the p.Ala57Thr variant is uncertain, available data suggest that it is more li kely to be benign. ACMG/AMP Criteria applied: BP4. |
| Labcorp Genetics |
RCV001857836 | SCV002121630 | uncertain significance | not provided | 2023-11-25 | 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 57 of the WFS1 protein (p.Ala57Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 252656). 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 80%. 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. |
| Clinical Genomics, |
RCV002509055 | SCV002769817 | benign | Wolfram syndrome 1 | criteria provided, single submitter | research | Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs372783392 in Wolfram's syndrome yet. | |
| Fulgent Genetics, |
RCV002479950 | SCV002783625 | uncertain significance | Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome | 2022-05-24 | criteria provided, single submitter | clinical testing |