Submissions for variant NM_006005.3(WFS1):c.2029G>A (p.Ala677Thr)

gnomAD frequency: 0.00004  dbSNP: rs757027394

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180289	SCV000232695	uncertain significance	not provided	2014-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765785	SCV000897174	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-02-12	criteria provided, single submitter	clinical testing
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV001328016	SCV001519349	uncertain significance	Childhood onset hearing loss	2021-07-08	criteria provided, single submitter	research	PP3 / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180289	SCV002281492	uncertain significance	not provided	2023-11-13	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 677 of the WFS1 protein (p.Ala677Thr). This variant is present in population databases (rs757027394, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of WFS1-related conditions (PMID: 26969326, 33046911). ClinVar contains an entry for this variant (Variation ID: 198834). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
GeneDx	RCV000180289	SCV002568505	uncertain significance	not provided	2022-02-22	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: 34837038, 26969326, 34426522, 33046911)
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003126571	SCV003802912	uncertain risk allele	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 rs757027394 in Wolfram's syndrome yet.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526628	SCV005039069	uncertain significance	not specified	2024-03-26	criteria provided, single submitter	clinical testing	Variant summary: WFS1 c.2029G>A (p.Ala677Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250488 control chromosomes (i.e. in 22 carriers) in the gnomAD database (v2.1 dataset). The variant, c.2029G>A, has been reported in the literature in heterozygous state in individuals affected with nonsyndromic hearing loss and type 2 diabetes (e.g. Sloan-Heggen_2016, Bonnefond_2020, Adeyemo_2021). These reports do not provide unequivocal conclusions about association of the variant with Wolfram Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26969326, 33046911, 34837038). ClinVar contains an entry for this variant (Variation ID: 198834). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000180289	SCV002036986	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000180289	SCV002037898	uncertain significance	not provided		no assertion criteria provided	clinical testing