Submissions for variant NM_006005.3(WFS1):c.1511C>T (p.Pro504Leu)

gnomAD frequency: 0.00001  dbSNP: rs28937892

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387727	SCV001588428	pathogenic	not provided	2024-10-30	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 504 of the WFS1 protein (p.Pro504Leu). This variant is present in population databases (rs28937892, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 9771706, 15277431, 24890733). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4512). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects WFS1 function (PMID: 16806192). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001387727	SCV001811037	likely pathogenic	not provided	2024-11-19	criteria provided, single submitter	clinical testing	Reported as heterozygous in two patients with type 1 diabetes (PMID: 31264968); Published functional studies demonstrate that P504L leads to increased degradation of the WFS1 protein (PMID: 16806192); 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: 15277431, 24890733, 31589614, 15151504, 11161832, 12955714, 9771706, 36208030, 36147510, 34746052, 37444722, 34258273, 31264968, 15605410, 28432734, 16806192)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243622	SCV002512480	pathogenic	Wolfram syndrome 1; Wolfram-like syndrome	2021-09-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM3 strong, PP1 supporting, PP3 supporting
Fulgent Genetics, Fulgent Genetics	RCV002496259	SCV002811728	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-04-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004770	SCV004122624	pathogenic	Wolfram syndrome 1	2023-10-09	criteria provided, single submitter	clinical testing	Variant summary: WFS1 c.1511C>T (p.Pro504Leu) 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 3.6e-05 in 249854 control chromosomes (gnomAD and publication data). c.1511C>T has been reported in the literature in multiple individuals affected with Wolfram Syndrome 1 (Inoue_1998, Gmez-Zaera_2001, Astuti_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in decreasing protein stability (Hofmann_2006) . The following publications have been ascertained in the context of this evaluation (PMID: 28432734, 11161832, 16806192, 9771706). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004770	SCV000024946	pathogenic	Wolfram syndrome 1	1998-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004737135	SCV005345930	pathogenic	WFS1-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The WFS1 c.1511C>T variant is predicted to result in the amino acid substitution p.Pro504Leu. This variant has been reported in the compound heterozygous state in multiple patients with Wolfram syndrome (Inoue et al. 1998. PubMed ID: 9771706; Chaussenot et al. 2014. PubMed ID: 24890733) and was also reported in two patients with type 1 diabetes (Table S6, Yu et al. 2019. PubMed ID: 31264968). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.