ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function

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 rs71524365 in Wolfram's syndrome yet.

The c.176C>T variant has not previously been reported in the literature and it has been deposited in ClinVar [ClinVar ID: 903895] as a Variant of Uncertain Significance (3 entries). The c.176C>T variant is observed in 6 alleles (0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.176C>T variant is located inexon 2 of this 8-exon gene and is predicted to replace a moderately conserved alanine amino acid with valine at position 59 p.(Ala59Val) in the encoded protein.In silico predictions are not in favor of the damaging effect for the p.(Ala59Val) variant [(CADD v1.6 = 15.94, REVEL = 0.205)]; however, there are no functional studies to support or refute these predictions. A different missense variant (p.Ala59Ser) affecting the same codon has been reported in ClinVar (Variation ID: 1320724) as a variant of Uncertain significance. Based on available evidence this c.176C>T p.(Ala59Val) variant identified in WFS1 is classified as a Variant ofUncertain Significance.

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 59 of the WFS1 protein (p.Ala59Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 903895). 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 not expected to disrupt WFS1 protein function with a negative predictive value of 95%. 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.