Submissions for variant NM_006005.3(WFS1):c.2206G>A (p.Gly736Ser)

gnomAD frequency: 0.00003  dbSNP: rs71532864

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001797328	SCV002038782	likely pathogenic	not provided	2024-06-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31264968, 15473915, 15605410, 32179840, 37185285, 37931151, Abali2023[article], 33841295, 8808601, 38162681, 35452662, 37383390, 36964972, 37444722, 10521293)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001797328	SCV002236433	pathogenic	not provided	2024-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 736 of the WFS1 protein (p.Gly736Ser). This variant is present in population databases (rs71532864, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 8808601, 10521293, 32179840). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1328696). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt WFS1 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly736 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15151504). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Department Of Endocrinology, Sanjay Gandhi Postgraduate Institute Of Medical Sciences	RCV003321872	SCV004025931	pathogenic	Wolfram syndrome 1	2023-08-15	criteria provided, single submitter	research	Missense variation in exon 8 of the WFS1 gene (chr4:g.6302001G>A) which replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 736 of the WFS1 protein (p.Gly736Ser). The observed variation has previously been reported in patients affected with Wolfram syndrome (PMID: 10521293, 31264968, 15605410, 32179840). This variant is present in population databases (rs71532864, gnomAD 0.006%). ClinVar contains an entry for this variant (Variation ID: 1328696). The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. PS1, PM1, PM2, PM3, PM5, PP3.
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	RCV001797328	SCV004100830	pathogenic	not provided	2022-08-21	criteria provided, single submitter	research