Submissions for variant NM_006005.3(WFS1):c.1124G>A (p.Arg375His)

gnomAD frequency: 0.00029  dbSNP: rs142671083

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615343	SCV000711249	uncertain significance	not specified	2017-09-14	criteria provided, single submitter	clinical testing	The p.Arg375His variant in WFS1 has been previously reported by our laboratory i n one individual with hearing loss. This variant has also been identified in 60/ 126648 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs142671083); however, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conser vation analyses do not provide strong support for or against an impact to the pr otein. In summary, the clinical significance of the p.Arg375His variant is uncer tain.
CeGaT Center for Human Genetics Tuebingen	RCV000762133	SCV000892391	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765778	SCV000897167	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-05-05	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174418	SCV001337556	uncertain significance	Monogenic diabetes	2018-09-05	criteria provided, single submitter	research	ACMG criteria: PP3 (10 predictors, REVEL=0.818 )=VUS
Invitae	RCV000762133	SCV001494165	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 375 of the WFS1 protein (p.Arg375His). This variant is present in population databases (rs142671083, gnomAD 0.05%). This missense change has been observed in individual(s) with WFS1-related coditions (PMID: 31264968, 31638168). ClinVar contains an entry for this variant (Variation ID: 504709). 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	RCV000762133	SCV001814117	uncertain significance	not provided	2019-08-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31638168, 31264968, 26435059)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000762133	SCV001740836	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762133	SCV001972566	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000762133	SCV002036812	uncertain significance	not provided		no assertion criteria provided	clinical testing