ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2663C>T (p.Ser888Leu)

gnomAD frequency: 0.00004  dbSNP: rs547089139
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198858 SCV000252561 uncertain significance not provided 2022-09-13 criteria provided, single submitter clinical testing Identified in a cohort of patients with presumed autosomal recessive sensorineural hearing loss in published literature (Sommen et al., 2016), but additional evidence is not available; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 27068579)
Invitae RCV000198858 SCV002219054 uncertain significance not provided 2023-10-09 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 888 of the WFS1 protein (p.Ser888Leu). This variant is present in population databases (rs547089139, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of deafness (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 215415). 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 expected to disrupt WFS1 protein function. 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.
MGZ Medical Genetics Center RCV002288801 SCV002580074 uncertain significance Wolfram-like syndrome 2021-10-05 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002492911 SCV002800883 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2021-10-28 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004528985 SCV004105804 uncertain significance WFS1-related disorder 2023-09-08 criteria provided, single submitter clinical testing The WFS1 c.2663C>T variant is predicted to result in the amino acid substitution p.Ser888Leu. This variant has been reported in an individual with hearing loss (Table S1, Sommen et al. 2016. PubMed ID: 27068579). It has also been reported in individual from population cohort from Turkey (Dataset 4, Kars et al. 2021. PubMed ID: 34426522). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6304185-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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