Submissions for variant NM_006005.3(WFS1):c.1693C>G (p.Leu565Val)

gnomAD frequency: 0.00031  dbSNP: rs200058166

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214468	SCV000272912	uncertain significance	not specified	2017-12-21	criteria provided, single submitter	clinical testing	The p.Leu565Val variant in WFS1 has been previously reported by our laboratory i n the heterozygous state in 1 individual with hearing loss. This variant has bee n identified in 7/33580 Latino chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org/; dbSNP rs200058166). Although this vari ant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation ana lysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu565Val variant is uncertain. ACMG /AMP criteria applied: none.
GeneDx	RCV001589140	SCV001823882	uncertain significance	not provided	2025-02-07	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30019023)
New York Genome Center	RCV001838992	SCV002099307	uncertain significance	Wolfram syndrome 1; Wolfram-like syndrome	2021-04-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001589140	SCV002167176	uncertain significance	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 565 of the WFS1 protein (p.Leu565Val). This variant is present in population databases (rs200058166, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 229638). 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) indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 80%. 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003126611	SCV003801426	uncertain 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 rs200058166 in Wolfram's syndrome yet.
Fulgent Genetics, Fulgent Genetics	RCV005031790	SCV005672323	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-04-18	criteria provided, single submitter	clinical testing