Submissions for variant NM_006005.3(WFS1):c.2020G>A (p.Gly674Arg)

gnomAD frequency: 0.00016  dbSNP: rs200672755

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197395	SCV000252537	pathogenic	not provided	2024-08-20	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in three siblings with moderate non-syndromic hearing loss in the literature, however, the variant did not segregate completely with hearing loss in the family and the pathogenicity was described as unclear (PMID: 24909696); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23429432, 22238590, 29563951, 27395765, 31264968, 11317350, 28802351, 12955714, 12073007, 31391115, 31589614, 34792487, 25211237, 26435059, 33538814, 34573359, 31765440, 31850070, 11161832, 36098976, 24909696, 34789499, 36208030, 36147510, 31343797, 33841295, 36729443)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625904	SCV000746483	likely pathogenic	WFS1-Related Spectrum Disorders	2017-12-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825499	SCV000966802	uncertain significance	not specified	2018-04-10	criteria provided, single submitter	clinical testing	The p.Gly674Arg variant has been previously reported in an individual with Wolfr am syndrome and an individual with hearing loss (de Heredia 2013, Hakli 2014); h owever, this variant is also present in 0.02% (62/276372) of the total chromosom es in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200672755). Two missense variants at the same position (Gly674Glu and G ly674Val) have been reported to segregate in families with hearing loss (Cryns 2 002). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, due to conflicting evidence, the clin ical significance of the p.Gly674Arg variant is uncertain. ACMG/AMP Criteria app lied: PP3; PM5; BS1_Supporting.
CeGaT Center for Human Genetics Tuebingen	RCV000197395	SCV001154167	likely pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375186	SCV001571792	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM5_Moderate, PP3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197395	SCV002237903	pathogenic	not provided	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 674 of the WFS1 protein (p.Gly674Arg). This variant is present in population databases (rs200672755, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 22238590, 25211237, 31391115). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215394). 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 expected to disrupt WFS1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV001789765	SCV002580111	likely pathogenic	Wolfram syndrome 1	2022-07-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517281	SCV003698529	uncertain significance	Inborn genetic diseases	2020-12-28	criteria provided, single submitter	clinical testing	The c.2020G>A (p.G674R) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to A substitution at nucleotide position 2020, causing the glycine (G) at amino acid position 674 to be replaced by an arginine (R). Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant Wolfram syndrome; however, the clinical significance for autosomal recessive Wolfram syndrome and autosomal dominant hearing loss is unclear. The p.G674R alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003884394	SCV004698090	pathogenic	Wolfram-like syndrome	2024-02-22	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PM5_STR,PS4_MOD,PM1,PP3
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816336	SCV005069547	likely pathogenic	Optic atrophy	2022-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816335	SCV005073446	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001789765	SCV005398154	pathogenic	Wolfram syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive Wolfram syndrome 1 (MIM#222300), and a dominant negative mechanism has also been suggested for heterozygous missense variants causing autosomal dominant Wolfram-like syndrome (MIM#614296). (I) 0108 - This gene is associated with both recessive and dominant disease. Wolfram syndrome 1 (MIM#222300) is recessive, whereas Wolfram-like syndrome (MIM#614296) is inherited in a dominant manner (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (65 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Wolframin cysteine-rich domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to a glutamic acid, a valine and a tryptophan have been reported in individuals with sensorineural hearing loss (PMID: 12073007, 34258273). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Wolfram syndrome (ClinVar, PMID: 22238590, 25211237, 31850070). It has also been reported as VUS in ClinVar and in a family with nonsydromic hearing loss (PMID: 24909696). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000197395	SCV005413638	pathogenic	not provided	2023-07-31	criteria provided, single submitter	clinical testing	PP1, PP3, PP4, PM2_moderate, PM3_strong, PS4_moderate
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796093	SCV005418726	likely pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3+PP1+PP4
Fulgent Genetics, Fulgent Genetics	RCV004796093	SCV005667525	likely pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-06-19	criteria provided, single submitter	clinical testing
Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre	RCV001175319	SCV001250637	pathogenic	Diabetes mellitus		no assertion criteria provided	research	PS1 PM2, PM5, PP3 PP5
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV001789765	SCV002032279	pathogenic	Wolfram syndrome 1	2021-11-25	no assertion criteria provided	research	Jewish Algerian origin. Compound heterozygossity with NM_006005.3:c.1088A>C. Congenital low-tone HL. Teenage onset mild vision problem.
PreventionGenetics, part of Exact Sciences	RCV004530182	SCV004119890	likely pathogenic	WFS1-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The WFS1 c.2020G>A variant is predicted to result in the amino acid substitution p.Gly674Arg. This variant has been reported in the compound heterozygous state in three patients with optic atrophy, two of which had a likely pathogenic truncating variant on the opposite allele (Table S2, Charif et al. 2021. PubMed ID: 33841295), as well as in the compound heterozygous state along with a likely pathogenic frameshift variant in a patient with Wolfram syndrome (Aloi et al. 2012. PubMed ID: 22238590). This variant has also been reported in the homozygous state in a patient with Wolfram syndrome (Galvez-Ruiz et al. 2017. PubMed ID: 29563951), and in the compound heterozygous state along with a potentially pathogenic missense variant in three patients with Wolfram syndrome from two different families (Zhang et al. 2019. PubMed ID: 31391115). This variant has been reported in the heterozygous state along with another potentially pathogenic missense variant in a patient with optic neuropathy (Lin et al. 2021. PubMed ID: 34573359), and a patient with Wolfram syndrome (Matsunaga et al. 2014. PubMed ID: 25211237), although phase was not reported in these individuals. However, this variant has also been reported in the homozygous state in a presumably unaffected individual of unknown age from a population study (Fattahi et al. 2019. PubMed ID: 31343797), and in the homozygous state in an unaffected individual from a family with Wolfram syndrome (Gómez-Zaera et al. 2001. PubMed ID: 11161832). This variant has been reported in the heterozygous state in three siblings with nonsyndromic hearing loss as well as their unaffected father and two other unaffected siblings (Häkli et al. 2014. PubMed ID: 24909696) and in a patient with type 1 diabetes (Table S6, Yu et al. 2019. PubMed ID: 31264968). Additionally, two different substitutions at the same amino acid position (Glu, Val) have been reported to segregate with autosomal dominant low-frequency sensorineural hearing loss in four and eight affected individuals from two different families, respectively (Cryns et al. 2002. PubMed ID: 12073007). This variant is reported in 0.049% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar this variant has conflicting interpretations of uncertain (2), likely pathogenic (5) and pathogenic (2) (https://www.ncbi.nlm.nih.gov/clinvar/variation/215394/). Taken together, we classify this variant as likely pathogenic for autosomal recessive and dominant WFS1-related disease, although penetrance may be incomplete in the homozygous or heterozygous state.