Submissions for variant NM_006005.3(WFS1):c.2620G>A (p.Ala874Thr)

gnomAD frequency: 0.00006  dbSNP: rs200775335

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000312654	SCV000336212	uncertain significance	not provided	2015-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000312654	SCV001780360	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26435059, 29563951, 34426522)
Invitae	RCV000312654	SCV002127360	uncertain significance	not provided	2024-01-25	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 874 of the WFS1 protein (p.Ala874Thr). This variant is present in population databases (rs200775335, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Wolfram-like syndrome (PMID: 29563951). ClinVar contains an entry for this variant (Variation ID: 283864). 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 with a positive predictive value of 95%. 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	RCV002480014	SCV002789499	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-04-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000312654	SCV004185218	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	WFS1: PM2
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV004584656	SCV005073826	pathogenic	Autosomal dominant nonsyndromic hearing loss 6	2024-06-13	criteria provided, single submitter	research	Pathogenic by Deafness Variation Databse based on PMID: 29563951