Submissions for variant NM_006005.3(WFS1):c.977C>T (p.Ala326Val)

gnomAD frequency: 0.00006  dbSNP: rs369795224

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727902	SCV000855408	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000727902	SCV001801681	uncertain significance	not provided	2021-05-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 32179840, 29850290, 28432734, 11920861, 15605410)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727902	SCV002315349	pathogenic	not provided	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 326 of the WFS1 protein (p.Ala326Val). This variant is present in population databases (rs369795224, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 28432734, 29850290, 32179840; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 592987). 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. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000727902	SCV004147632	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	WFS1: PP1:Moderate, PS3:Supporting, BP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788150	SCV005399562	likely pathogenic	Wolfram syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive Wolfram syndrome 1 (MIM#222300), and a dominant negative mechanism has also been suggested for heterozygous missense variants causing autosomal dominant Wolfram-like syndrome (MIM#614296). (I) 0108 - This gene is associated with both recessive and dominant disease. Wolfram syndrome 1 (MIM#222300) is recessive, whereas Wolfram-like syndrome (MIM#614296) is inherited in a dominant manner (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 30 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been classified as a VUS (ClinVar), however it has also been reported as likely pathogenic in at least three individuals with autosomal recessive Wolfram syndrome 1 (MIM#222300), once in compound heterozygosity with p.(Gly437Arg) (PMID: 28432734, PMID: 29850290, PMID: 32179840). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000727902	SCV005413637	likely pathogenic	not provided	2024-04-17	criteria provided, single submitter	clinical testing	PM2_moderate, PM3, PS4_moderate