Submissions for variant NM_006005.3(WFS1):c.505G>A (p.Glu169Lys)

gnomAD frequency: 0.00005  dbSNP: rs148953711

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196664	SCV000252511	pathogenic	not provided	2024-04-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: disrupted localization to the endoplasmic reticulum and impaired interaction with SEC24 (PMID: 34848728); This variant is associated with the following publications: (PMID: 27045389, 26875006, 30245029, 11317350, 12955714, 31313226, 27810688, 15473915, Pizzolanti2014[Case Report], 34006618, 10521293, 35469785, 28432734, 34848728)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196664	SCV002241265	pathogenic	not provided	2023-04-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 215376). This missense change has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 26875006, 27045389, 28432734). This variant has been reported in individual(s) with autosomal dominant Wolfram-like syndrome (PMID: 27810688); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs148953711, gnomAD 0.005%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 169 of the WFS1 protein (p.Glu169Lys).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786525	SCV005400318	pathogenic	Wolfram syndrome 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive Wolfram syndrome (MIM#222300). Dominant-negative is suggested for heterozygous missense variants causing autosomal dominant Wolfram-like syndrome (MIM#614296) (PMID: 32219690). (I) 0108 - This gene is associated with both recessive and dominant disease. Both deafness 6/14/38 (MIM#600965) and Wolfram-like syndrome (MIM#614296) are inherited in an autosomal dominant manner while Wolfram syndrome 1 (MIM#222300) is autosomal recessive. A clear genotype-phenotype correlation is currently unestablished. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3: 8 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Wolframin Sel1-like repeat (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple compound heterozygous families with autosomal recessive Wolfram syndrome (MIM#222300) (PMIDs: 21446023, 28432734, 31266054, 35469785); and at least one heterozygous family with diabetes only (PMID: 27810688). It has also been classified as likely pathogenic and pathogenic by diagnostic laboratories in ClinVar. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant NM_006005.3:c.605A>G; p.(Glu202Gly)) in a recessive disease. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005031738	SCV005664682	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-04-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530178	SCV004120871	likely pathogenic	WFS1-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The WFS1 c.505G>A variant is predicted to result in the amino acid substitution p.Glu169Lys. This variant has been reported in a patient with Wolfram syndrome (WS) who also harbored two other rare missense variants, although family studies were not performed to determine phase (Hardy. 1999. PubMed ID: 10521293). This variant along with a second potentially causative variant was also reported in two siblings with optic atrophy, diabetes, and neurogenic bladder, although phase of the variants was not reported (Majander. 2016. PubMed ID: 26875006). This variant was also reported in a second patient with WS as a de novo variant in trans with a missense and nonsense variant inherited from an unaffected parent (Pizzolanti. 2014. J Genet Syndr Gene Ther 5:245). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.