Submissions for variant NM_006005.3(WFS1):c.1265C>T (p.Ala422Val)

gnomAD frequency: 0.00029  dbSNP: rs150368988

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445460	SCV000537009	uncertain significance	Monogenic diabetes	2016-03-04	criteria provided, single submitter	research	ACMG Criteria: PP3, BP4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825498	SCV000966801	uncertain significance	not specified	2018-11-13	criteria provided, single submitter	clinical testing	The p.Ala422Val variant in WFS1 has not been previously reported in individuals with hearing loss or Wolfram syndrome, but has been identified in 0.035% (45/129 150) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 393388). Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, the clinical significance of the p. Ala422Val variant is uncertain. ACMG/AMP Criteria applied: None.
Athena Diagnostics Inc	RCV000993556	SCV001146646	uncertain significance	not provided	2019-04-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001157339	SCV001318901	uncertain significance	Autosomal dominant nonsyndromic hearing loss 6	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001157340	SCV001318902	uncertain significance	WFS1-Related Spectrum Disorders	2018-01-12	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000993556	SCV001805362	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	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
Genetic Services Laboratory, University of Chicago	RCV000825498	SCV002064895	uncertain significance	not specified	2021-12-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the WFS1 gene demonstrated a sequence change, c.1265C>T, in exon 8 that results in an amino acid change, p.Ala422Val. This sequence change has been described in the gnomAD database with a frequency of 0.03% in the non-Finnish European subpopulation (dbSNP rs150368988). The p.Ala422Val change affects a moderately conserved amino acid residue located in a domain of the WFS1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala422Val substitution. This sequence change does not appear to have been previously described in individuals with WFS1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala422Val change remains unknown at this time.
Invitae	RCV000993556	SCV002432223	likely benign	not provided	2023-12-11	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509384	SCV002817344	uncertain significance	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 rs150368988 in Wolfram's syndrome yet.
Revvity Omics, Revvity	RCV000993556	SCV003823771	uncertain significance	not provided	2022-04-07	criteria provided, single submitter	clinical testing