ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2171C>T (p.Pro724Leu) (rs28937890)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756934 SCV000884924 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing The WFS1 c.2171C>T; p.Pro724Leu variant (rs28937890) has been previously observed as a homozygote in a pair of siblings from a consanguineous Japanese family with a Wolfram syndrome phenotype (minimally, juvenile-onset diabetes mellitus and optic atrophy; Inoue 1998). Numerous functional studies have demonstrated that this variant effects WFS1 protein stability (Hofmann 2006), localization (Fonseca 2005), increased tendency for aggregation (De Franco 2017), and interactions with ATF6 (Fonseca 2010). This variant is found in the general population with an overall allele frequency of 0.003% (8/243,604 alleles) in the Genome Aggregation Database. Based on the available information, the clinical significance of this variant cannot be determined with certainty. De Franco E et al. Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes. 2017 Jul;66(7):2044-2053. Fonseca SG et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005 Nov 25;280(47):39609-15 Fonseca SG et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010 Mar;120(3):744-55. Hofmann S and Bauer M. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin. FEBS Lett. 2006 Jul 10;580(16):4000-4. Inoue H et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998 Oct;20(2):143-8.
Athena Diagnostics Inc RCV000756934 SCV001477211 pathogenic not provided 2020-09-04 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family.
OMIM RCV000004767 SCV000024943 pathogenic Wolfram syndrome 1 1998-10-01 no assertion criteria provided literature only

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