4-6301467-C-T

Position:

chr4-6301467-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM5PP3BP4_ModerateBS2

The NM_006005.3(WFS1):c.1672C>T(p.Arg558Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000348 in 1,612,648 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R558H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00035 ( 4 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:3

Conservation

PhyloP100: 4.16

Variant links:

Genes affected

WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

WFS1 links:

WFS1 (HGNC:):

WFS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301468-G-A is described in Lovd as [Pathogenic].

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.24366054).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1672C>T	p.Arg558Cys	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 linkuse as main transcript	c.1672C>T	p.Arg558Cys	missense_variant	8/8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.1672C>T	p.Arg558Cys	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000671

AC:

168

AN:

250552

Hom.:

AF XY:

0.000730

AC XY:

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0133

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000351

AC:

512

AN:

1460386

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

273

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0137

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000800

Gnomad4 OTH exome

AF:

0.000927

GnomAD4 genome

AF:

0.000328

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.000431

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	The WFS1 c.1672C>T; p.Arg558Cys variant (rs199946797) is reported in the literature in the compound heterozygous or homozygous state in several individuals affected with Wolfram syndrome, although this variant is often associated with a mild or atypical, later-onset form of disease (Astuti 2017, Bansal 2018, Cano 2007, Chaussenot 2015, Grenier 2016, Pan 2019, Ustaoglu 2020, Wilf-Yarkoni 2021, Zhang 2022). This variant is found in the general population with an overall allele frequency of 0.063% (177/281960 alleles), and may be a founder variant in the Ashkenazi Jewish population with an allele frequency of 1.34% (139/10366 alleles, including a single homozygote) in the Genome Aggregation Database. This variant is also reported in ClinVar (Variation ID: 198835), and computational analyses predict that this variant is deleterious (REVEL: 0.816). Additionally, another variant at this codon (c.1673G>A; p.Arg558His) has been reported in individuals with Wolfram syndrome and is considered pathogenic (Grenier 2016, Zhang 2022). Based on available information, this variant is considered to be likely pathogenic. References: Astuti D et al. Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. Hum Mutat. 2017 Jul;38(7):764-777. PMID: 28432734. Bansal V et al. Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals. Diabetologia. 2018 Oct;61(10):2180-2188. PMID: 30014265. Cano et al. Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome. Am J Med Genet A. 2007 Jul 15;143A(14):1605-12. Chaussenot et al. Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders. Clin Genet. 2015 May;87(5):430-9. Grenier J et al. WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity. Ophthalmology. 2016 Sep;123(9):1989-98. PMID: 27395765. Pan YD et al. Compound heterozygous mutations in WFS1 cause atypical Wolfram syndrome. Chin Med J (Engl). 2019 Oct 20;132(20):2508-2509. PMID: 31567480. Ustaoglu M et al. Ophthalmic, systemic, and genetic characteristics of patients with Wolfram syndrome. Eur J Ophthalmol. 2020 Sep;30(5):1099-1105. PMID: 30957632. Wilf-Yarkoni A et al. Mild Phenotype of Wolfram Syndrome Associated With a Common Pathogenic Variant Is Predicted by a Structural Model of Wolframin. Neurol Genet. 2021 Mar 19;7(2):e578. PMID: 33763535. Zhang X et al. Comprehensive Genetic Analysis Unraveled the Missing Heritability in a Chinese Cohort With Wolfram Syndrome 1: Clinical and Genetic Findings. Invest Ophthalmol Vis Sci. 2022 Sep 1;63(10):9. PMID: 36098976. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 558 of the WFS1 protein (p.Arg558Cys). This variant is present in population databases (rs199946797, gnomAD 1.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of Wolfram syndrome (PMID: 17568405, 21446023, 23596069, 27395765, 28432734, 29207974, 30014265, 30957632, 33763535, 34404380). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 30014265). This variant might be associated with later onset or milder phenotypes. ClinVar contains an entry for this variant (Variation ID: 198835). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. This variant disrupts the p.Arg558 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15277431, 31567480). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2022	Observed in apparent homozygous state in multiple patients with early-onset diabetes with or without other features of Wolfram syndrome, supporting the conclusion that p.(R558C) causes a mild form of Wolfram syndrome, with later onset of diabetes (17.8 +/- 8.3 years) and absence of optic atrophy in most homozygous individuals of Ashkenazi Jewish ancestry (Bansal et al., 2018); Observed in heterozygous state in an individual with ataxia and in an individual with familial schizophrenia (Fogel et al., 2014; Torres et al., 2001), however it is unclear whether the variant contributed to these individuals' phenotypes; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25133958, 21446023, 28432734, 24890733, 31264968, 27395765, 26435059, 17568405, 30245029, 22226368, 30957632, 12754709, 15277431, 19344068, 32518033, 32335055, 33046911, 34556497, 31980526, 33763535, 11244483, 30014265, 34746052, 35018440, 35206658, Kitamura2021[preprint], 33538814, 35602877, 29207974) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2021	- -

Wolfram syndrome 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 25, 2022	The c.1672C>T variant identified in WFS1 has been reported in homozygous as well as compound heterozygous states in at least 20 individuals with late-onset Wolfram syndrome [PMID: 17568405, 21446023, 22226368, 24890733, 30014265, 30957632, 33763535], and it has been deposited in ClinVar [ClinVarID:198835]. The c.1672C>T is observed in 218 alleles (~0.05% minor allele frequency (MAF) with 1 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2), with having >1% MAF in individuals of Ashkenazi Jewish ancestry suggesting it might be a founder variant in that population. Of note, those population databases include individuals with late onset disorders like diabetes mellitus. The c.1672C>T variant is located in exon 8 of this 8-exon gene and predicted to replace an evolutionarily conserved arginine aminoacid with cysteine at position 558 (p.(Arg558Cys)) in the cytoplasmic linker region connecting transmembrane domains VI and VII of the encoded protein [see Figure 1 in PMID:20301750]. In silico predictions are moderately in favor of damaging effect for p.(Arg558Cys) [CADD v1.6 = 25.5,REVEL = 0.816]; however, there are no functional studies to support or refute these predictions. Another variant affecting the same amino acid residue(c.1673G>A:p.(Arg558His)) has also been reported in the literature [PMID: 12754709, 21446023, 24890733, 31567480] and ClinVar [ClinVar ID: 427051] in individuals with late-onset Wolfram syndrome. Based on available evidence the c.1672C>T p.(Arg558Cys) variant identified in WFS1 is classified as Pathogenic for autosomal recessive late-onset Wolfram syndrome. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Dec 19, 2023	- -

WFS1-Related Spectrum Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 10, 2018

The WFS1 c.1672C>T (p.Arg558Cys) missense variant has been reported in at least seven studies and is found in a total of 15 individuals with Wolfram syndrome, including in a homozygous state in at least ten individuals, in a compound heterozygous state in two, and in a heterozygous state in three individuals (Cano et al. 2007; Ganie et al. 2009; Chaussenot et al. 2011; Lieber et al. 2012; Chaussenot et al. 2015; Grenier et al. 2016; Bansal et al. 2018). The variant was also reported in a heterozygous state in one individual with schizophrenia (Torres et al. 2001) and in another individual with cerebellar ataxia (Fogel et al. 2014). The p.Arg558Cys is identified with a very mild phenotype that authors indicate may be difficult to diagnose clinically (Bansal et al. 2018). The p.Arg558Cys variant was found in 58 alleles from 2589 control sample and is reported at a frequency of 0.00084 in the European (non-Finnish) population of the Exome Aggregation Consortium and 0.013790 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Arg558Cys variant is classified as pathogenic for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 03, 2024

- -

Diabetes mellitus

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre

PS1 PM2 PP3 PP4 -

WFS1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2023

The WFS1 c.1672C>T variant is predicted to result in the amino acid substitution p.Arg558Cys. This variant was reported in the compound heterozygous and homozygous states in individuals with features of Wolfram syndrome (Cano et al. 2007. PubMed ID: 17568405; Lieber et al 2012. PubMed ID: 22226368; Ustaoglu et al 2019. PubMed ID: 30957632). This variant has also been reported, with uncertain significance, in an individual with sporadic ataxia (Fogel et al 2014. PubMed ID: 25133958) and in an individual with schizophrenia (Torres et al 2001. PubMed ID: 11244483). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote. This variant in the homozygous state was found to significantly increase risk for type 1 diabetes in a cohort of Ashkenazi Jewish patients, although age at diabetes diagnosis was later than usual and other features of Wolfram syndrome were absent in most patients, suggesting this variant has a mild effect compared to other Wolfram syndrome causative variants (Bansal et al. 2018. PubMed ID: 30014265). This variant is interpreted as likely pathogenic. -

Optic atrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Wolfram syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 11, 2016

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 05, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg558Cys variant in WFS1 has been previously reported in the homozygous or compound hete rozygous state in 5 individuals with Wolfram syndrome, at least 3 of whom were r eported to have late onset disease (Cano 2007, Chaussenot 2011, Lieber 2012, Cha ussenot 2015, Astuti 2017, Oakley 2017). It has also been identified in at least 2 individuals with nonsyndromic optic atrophy and 1 individual with progressive cerebellar ataxia (Fogel 2014, Grenier 2016, Sharma 2017). Additionally, our la boratory has identified the p.Arg558Cys variant in the heterozygous state in 2 i ndividuals with apparently nonsyndromic hearing loss, 1 of whom had an alternate explanation for their hearing loss. In vitro functional studies and in silico p rediction tools provide some evidence that the variant may impact protein functi on (Qian 2015, Sharma 2017); however, these types of assays may not accurately r epresent biological function. This variant has been identified in 1.4% (140/1015 0) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database, including 1 homozygous individual (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1999 46797). It should be noted that the gnomAD database may include individuals with late onset or adult disease such as diabetes mellitus and psychiatric disorders (http://gnomad.broadinstitute.org/about). In summary, while there is some suspi cion for a pathogenic role, because of its high frequency in the Ashkenazi Jewis h population and limited functional data, the clinical significance of this vari ant is uncertain. -

Type 2 diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 10, 2022

The c.1672C>T (p.Arg558Cys) missense variant identified in WFS1 has been reported in homozygous as well as in compound heterozygous states in individuals affected with autosomal recessive Wolfram syndrome [PMID: 30957632, 17568405, 21446023], reported as heterozygous in individuals affected with autosomal dominant Wolfram-like syndrome [PMID: 27395765], in three individuals in a cohort of 1019 patients with type 1 diabetes [PMID:31264968] and in a single patient in a large cohort of type 2 diabetes patients [PMID:33046911]. It was also reported as a variant of uncertain significance in an individual affected with ataxia and polyneuropathy and in an individual affected with familial schizophrenia [PMID: 25133958, 11244483]. The variant has 0.0003284 allele frequency in the gnomAD(v3) database (50 out of 152262 heterozygous alleles, no homozygotes), 0.0006277 allele frequency in the gnomAD(v2) database (177 out of 281960 heterozygous alleles,1 homozygote) and 0.01341 allele frequency in the Ashkenazi Jewish subpopulation represented in gnomAD(v2) database (139 out of 10366 heterozygous alleles, 1 homozygous allele). Multiple independent laboratories have reported this variant in the ClinVar database with conflicting interpretations of pathogenicity for WFS1-related disorders [Variation ID: 198835; Pathogenic = 2, Likely pathogenic = 2, and Uncertain significance = 3]. This variant replaces highly conserved arginine residue [Arg558] and is predicted deleterious by multiple in silico tools (CADD score = 32, REVEL score = 0.816). Based on the available evidence,the heterozygous c.1672C>T (p.Arg558Cys) missense variant identified in the WFS1 gene is reported as a Variant of Uncertain Significance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.97

MVP

1.0

ClinPred

0.20

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over