Submissions for variant NM_006005.3(WFS1):c.683G>A (p.Arg228His)

gnomAD frequency: 0.00090  dbSNP: rs150771247

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724125	SCV000231712	uncertain significance	not provided	2018-02-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000724125	SCV000252516	likely benign	not provided	2021-11-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25133958, 33112832, 18544103)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000200201	SCV000272924	uncertain significance	not specified	2017-07-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg228His var iant in WFS1 has been previously identified in 1 individual with hearing loss an d hypothyroidism (LMM unpublished data) and 1 individual with cerebellar ataxia who also had some clinical features associated with Wolfram syndrome (Fogel 2014 ). Neither individual carried a second, clinically significant variant in the WF S1 gene (while the proband reported by Fogel et al had two additional WFS1 varia nts, our laboratory classifies these variants as benign based on high frequency in the African American population). The p.Arg228His variant has also been ident ified in 0.15% (181/122852) of European chromosomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150771247). Computational prediction tools and conservation analyses do not p rovide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg228His variant is uncertain, its frequenc y in the general population and identification in the homozygous state in 1 indi vidual from the general population suggests that it is more likely to be benign.
Fulgent Genetics, Fulgent Genetics	RCV000515386	SCV000611535	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2017-05-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724125	SCV000884922	uncertain significance	not provided	2019-10-02	criteria provided, single submitter	clinical testing	The WFS1 p.Arg228His variant (rs150771247) has been reported in one individual with a diagnosis of cerebellar ataxia who also harbored two high frequency WFS1 variants on the other allele (Fogel 2014). The p.Arg228His variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.15% in the non-Finnish European population (identified in 181 out of 122,852 chromosomes with 1 homozygote), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 198190). The arginine at codon 228 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the WFS1 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the WFS1 variant cannot be determined with certainty.
CeGaT Center for Human Genetics Tuebingen	RCV000724125	SCV001154160	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	WFS1: PM2
Illumina Laboratory Services, Illumina	RCV001155463	SCV001316890	uncertain significance	WFS1-Related Spectrum Disorders	2018-01-13	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	RCV001155464	SCV001316891	likely benign	Autosomal dominant nonsyndromic hearing loss 6	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000724125	SCV001541702	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537488	SCV004752569	likely benign	WFS1-related disorder	2023-05-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200201	SCV004803708	uncertain significance	not specified	2024-01-23	criteria provided, single submitter	clinical testing	Variant summary: WFS1 c.683G>A (p.Arg228His) results in a non-conservative amino acid change located in the Wolframin, EF-hand domain (IPR045460) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 1610506 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes (gnomAD v4). c.683G>A has been reported as a single heterozygous variant in one individual with early onset dementia, optic atrophy, and sensorineural hearing loss, and was at a compound heterozygous along with a second pathogenic variant in an individual with recessive WFS1-related disorders (example, Astuti_2017, Fogel_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Wolfram Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28432734, 25133958). ClinVar contains an entry for this variant (Variation ID: 198190). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000023512	SCV000044803	pathogenic	Wolfram-like syndrome	2008-06-01	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000724125	SCV002036015	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724125	SCV002037793	likely benign	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200201	SCV003839224	uncertain significance	not specified	2022-09-07	no assertion criteria provided	clinical testing	DNA sequence analysis of the WFS1 gene demonstrated a sequence change, c.683G>A, in exon 6 that results in an amino acid change, p.Arg228His. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the European subpopulation, including one homozygous individual (dbSNP rs150771247). The p.Arg228His 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.Arg228His substitution. The p.Arg228His change as been reported in one individual with dementia, optic atrophy and sensorineural hearing loss. However, a second clearly pathogenic variant in the WFS1 gene was not identified (PMID: 25133958). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg228His change remains unknown at this time. Biallelic pathogenic variants in WFS1 have been associated with autosomal recessive Wolfram syndrome, which is characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness (OMIM# 222300). Heterozygous pathogenic variants in WFS1 have also been associated with autosomal dominant Wolfram-like syndrome (OMIM# 614296) and sensorineural hearing loss (OMIM# 600965).