ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs28937892
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001387727 SCV001588428 pathogenic not provided 2023-10-05 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). 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. 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 2023-09-06 criteria provided, single submitter clinical testing Reported as heterozygous in two patients with type 1 diabetes (Yu et al., 2019); Published functional studies demonstrate that P504L leads to increased degradation of the WFS1 protein (Hofmann et al., 2006); 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, 16806192, 11161832, 15605410, 12955714, 9771706, 31264968, 36208030, 36147510, 34746052, 37444722, 34258273)
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

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