ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2119G>A (p.Val707Ile)

gnomAD frequency: 0.00007  dbSNP: rs71524377
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001853208 SCV000252496 uncertain significance not provided 2025-02-05 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31850070, 20738327, 23429432, 30245029, 18806274, 17603484, 12955714, 20301750, 18060660, 33879153)
Illumina Laboratory Services, Illumina RCV001157674 SCV001319270 uncertain significance Autosomal dominant nonsyndromic hearing loss 6 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001157675 SCV001319271 uncertain significance WFS1-Related Spectrum Disorders 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001853208 SCV002160330 uncertain significance not provided 2024-03-02 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 707 of the WFS1 protein (p.Val707Ile). This variant is present in population databases (rs71524377, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 215367). 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 with a negative 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003128189 SCV003804224 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 rs71524377 in Wolfram's syndrome yet.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001853208 SCV004564263 uncertain significance not provided 2023-01-06 criteria provided, single submitter clinical testing The WFS1 c.2119G>A; p.Val707Ile variant (rs71524377) is reported in cis to a frameshift WFS1 variant in several individuals with Wolfram syndrome or non-syndromic diabetes (Zalloua 2008). This variant is also reported in ClinVar (Variation ID: 215367). It is observed in the general population with an overall allele frequency of 0.004% (11/281244 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.579). Due to limited information the clinical significance of this variant is uncertain at this time. References: Zalloua PA et al. WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon. Hum Mol Genet. 2008 Dec 15;17(24):4012-21. PMID: 18806274.
Fulgent Genetics, Fulgent Genetics RCV005031735 SCV005667538 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2024-03-07 criteria provided, single submitter clinical testing

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