Submissions for variant NM_006005.3(WFS1):c.2654C>T (p.Pro885Leu)

gnomAD frequency: 0.00002  dbSNP: rs372855769

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503566	SCV000597981	likely pathogenic	Wolfram syndrome	2016-05-11	criteria provided, single submitter	clinical testing
Invitae	RCV001857186	SCV002236670	pathogenic	not provided	2022-12-14	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 10521293, 28432734). This variant is present in population databases (rs372855769, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 885 of the WFS1 protein (p.Pro885Leu). ClinVar contains an entry for this variant (Variation ID: 437297). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WFS1 function (PMID: 16806192). 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 expected to disrupt WFS1 protein function.
Fulgent Genetics, Fulgent Genetics	RCV002506232	SCV002807350	likely pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2021-11-18	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003233655	SCV003932158	pathogenic	Wolfram syndrome 1	2023-02-28	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM3_Supporting, PP3
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335435	SCV004046440	pathogenic	Autosomal dominant nonsyndromic hearing loss 6		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous and homozygous change in patients with Wolfram-like Syndrome/ Wolfram Syndrome (PMID: 10521293, 30773290, 28432734). In vitro analysis illustrated that the c.2654C>T (p.Pro885Leu) variant results in reduce protein expression affecting WFS1 function (PMID: 16806192). The c.2654C>T (p.Pro885Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/249382) and thus is presumed to be rare. The c.2654C>T (p.Pro885Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2654C>T (p.Pro885Leu) variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001857186	SCV004185219	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	WFS1: PM2, PM3, PP4, PS3:Supporting
Yale Center for Mendelian Genomics, Yale University	RCV001849390	SCV002106595	likely pathogenic	Wolfram-like syndrome	2019-02-14	no assertion criteria provided	literature only