Submissions for variant NM_006005.3(WFS1):c.1993A>C (p.Thr665Pro)

gnomAD frequency: 0.00004  dbSNP: rs369656458

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001153357	SCV001314643	uncertain significance	WFS1-Related Spectrum Disorders	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001153358	SCV001314644	uncertain significance	Autosomal dominant nonsyndromic hearing loss 6	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000722247	SCV002133027	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 591071). This missense change has been observed in individual(s) with type 1 diabetes (PMID: 31264968). This variant is present in population databases (rs369656458, gnomAD 0.2%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 665 of the WFS1 protein (p.Thr665Pro).
New York Genome Center	RCV002468026	SCV002764337	uncertain significance	Wolfram syndrome 1; Type 2 diabetes mellitus	2021-08-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000722247	SCV004031563	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Identified in an individual from a cohort of patients with type 1 diabetes, however additional clinical information and segregation data were not included (Yu et al., 2019); 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)
Gharavi Laboratory, Columbia University	RCV000722247	SCV000853378	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research