Submissions for variant NM_006005.3(WFS1):c.2470G>A (p.Glu824Lys)

gnomAD frequency: 0.00002  dbSNP: rs367547063

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152700	SCV000202079	uncertain significance	not specified	2013-06-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Glu824Lys i n WFS1 has not been reported in affected individuals, but has been identified in 0.01% (1/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although thi s variant has been seen in this cohort, it should be noted that for diseases wit h clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. Computati onal analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyP hen2, and SIFT) do not provide strong support for or against an impact to the pr otein. In summary, additional information is needed to fully assess the clinical significance of this variant.
Eurofins Ntd Llc (ga)	RCV000726782	SCV000702984	uncertain significance	not provided	2016-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000726782	SCV001812758	uncertain significance	not provided	2020-07-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31363008)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726782	SCV002184091	uncertain significance	not provided	2021-08-09	criteria provided, single submitter	clinical testing	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. This sequence change replaces glutamic acid with lysine at codon 824 of the WFS1 protein (p.Glu824Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs367547063, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of Wolfram/Wolfram-like syndrome (PMID: 31363008). ClinVar contains an entry for this variant (Variation ID: 166612). 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	RCV002498721	SCV002775703	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-03-25	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003147360	SCV003804398	likely risk allele	Wolfram syndrome 1		criteria provided, single submitter	research	Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs367547063 in Wolfram's syndrome yet.