Submissions for variant NM_006005.3(WFS1):c.1831C>T (p.Arg611Cys)

gnomAD frequency: 0.00014  dbSNP: rs144993516

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001157549	SCV001319137	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.
Illumina Laboratory Services, Illumina	RCV001157550	SCV001319138	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.
GeneDx	RCV001570232	SCV001794487	uncertain significance	not provided	2019-11-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in the heterozygous state in a patient with optic atrophy and tremor, however, additional clinical features and segregation information were not included for this patient (Galvez-Ruiz et al., 2018); Identified in the heterozygous state in a patient with autosomal dominant non-syndromic hearing loss, however, no additional information regarding this patient's hearing loss or family history was provided (Sloan-Heggen et al., 2016); This variant is associated with the following publications: (PMID: 29563951, 26969326)
Invitae	RCV001570232	SCV002281128	uncertain significance	not provided	2022-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 611 of the WFS1 protein (p.Arg611Cys). This variant is present in population databases (rs144993516, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of WFS1-related conditions (PMID: 29563951). ClinVar contains an entry for this variant (Variation ID: 907591). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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	RCV002491456	SCV002797009	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-05-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001570232	SCV003823762	uncertain significance	not provided	2021-01-06	criteria provided, single submitter	clinical testing