Submissions for variant NM_006005.3(WFS1):c.1820C>T (p.Pro607Leu)

gnomAD frequency: 0.00019  dbSNP: rs373862003

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038645	SCV000062323	uncertain significance	not specified	2013-03-09	criteria provided, single submitter	clinical testing	The Pro607Leu variant in WFS1 has not been reported in affected individuals, but has been identified in 1/8600 European American chromosomes from a broad popula tion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. In summary, addit ional information is needed to fully assess the clinical significance of the Pro 607Leu variant.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174424	SCV001337562	uncertain significance	Monogenic diabetes	2018-09-28	criteria provided, single submitter	research	ACMG criteria: PP3 (0.846 + 9 predictors), PM2_supporting (based on ClinGen HL approved rules 9/28/18, says can use PM2 as supporting if MAF is <0.007% and MAF of c.1820C>T in gnomAD is 0.0069%)= VUS Note: in PMID 26969326, variant ID'd in patient with sporadic NSHL, in trans with other WFS1 variant (c.2603G>A p.R868H; has REVEL score of 0.877/PP3, can use PM2-supporting, also VUS)
GeneDx	RCV001588853	SCV001825767	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing	Identified in patients with hearing loss or congenital cataracts in published literature; patients were also heterozygous for WFS1 p.(R868H); it is unknown if the two variants are on the same allele (in cis) or on opposite alleles (in trans) (PMID: 36729443, 26969326, 36597107); 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: 26435059, 36729443, 37719678, 36597107, 26969326)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001588853	SCV002260412	uncertain significance	not provided	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 607 of the WFS1 protein (p.Pro607Leu). This variant is present in population databases (rs373862003, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of non-syndromic hearing loss (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 45441). 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 80%. This variant disrupts the p.Pro607 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707373). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV002482999	SCV002793670	likely pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-06-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513506	SCV003743476	uncertain significance	Inborn genetic diseases	2021-05-10	criteria provided, single submitter	clinical testing	Identified in the heterozygous state with a second WFS1 variant in a patient with sporadic non-syndromic hearing loss (Sloan-Heggen, 2016)._x000D_ _x000D_ Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038645	SCV005394647	uncertain significance	not specified	2024-09-25	criteria provided, single submitter	clinical testing	Variant summary: WFS1 c.1820C>T (p.Pro607Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251406 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WFS1 causing Wolfram Syndrome 1, allowing no conclusion about variant significance. c.1820C>T has been reported in the literature in several individuals undergoing multigene panel testing for hearing loss or inherited eye diseases (congenital cataracts), where it is frequently reported together with c.2603G>A (p.Arg868His), although phase has not been specified (e.g. Sloan-Heggen_2016, Li_2023, Ma_2023). These reports do not provide unequivocal conclusions about association of the variant with Wolfram Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36729443, 36597107, 26969326). ClinVar contains an entry for this variant (Variation ID: 45441). Based on the evidence outlined above, the variant was classified as uncertain significance.