4-6277579-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_006005.3(WFS1):c.124C>T(p.Arg42*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,583,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

WFS1
NM_006005.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1O:1

Conservation

PhyloP100: 0.594

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Wolfram-like syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
Wolfram syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
autosomal dominant nonsyndromic hearing loss 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cataract 41
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Wolfram syndrome 1
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
type 2 diabetes mellitus
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

WFS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 4-6277579-C-T is Pathogenic according to our data. Variant chr4-6277579-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.124C>T	p.Arg42*	stop_gained	Exon 2 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 link	c.124C>T	p.Arg42*	stop_gained	Exon 2 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.124C>T	p.Arg42*	stop_gained	Exon 2 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000925

AC:

AN:

194514

AF XY:

0.000134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000622

AC:

AN:

1431560

Hom.:

Cov.:

AF XY:

0.0000762

AC XY:

AN XY:

709028

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32892

American (AMR)

AF:

0.0000983

AC:

AN:

40706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.00

AC:

AN:

38246

South Asian (SAS)

AF:

0.0000245

AC:

AN:

81668

European-Finnish (FIN)

AF:

0.0000200

AC:

AN:

50088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000720

AC:

AN:

1097440

Other (OTH)

AF:

0.0000506

AC:

AN:

59278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.0000586

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

May 28, 2025

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 21, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in the heterozygous state in a patient with chronic progressive external ophthalmoplegia in the published literature, however, familial segregation studies could not be performed, and authors indicate that the association of this variant with the patient's phenotype is uncertain (Heighton et al., 2019); Identified in the heterozygous state in a patient with intellectual disability and autism spectrum disorder, however segregation of this variant is unknown and the patient was not reported with other features of a WFS1-related disorder (Valentino et al., 2021); Identified in a study of type 2 diabetics and controls in the literature (Fawcett et al., 2010); however, no specific information was provided; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31980526, 33031055, 36208030, 34556497, 35206658, 36294752, 31521625, 34356170, 20028947)

Sep 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg42*) in the WFS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WFS1 are known to be pathogenic (PMID: 12955714). This variant is present in population databases (rs71530923, gnomAD 0.01%). This variant has not been observed in the literature in individuals with autosomal recessive WFS1-related conditions. This variant has been reported in individual(s) with clinical features of autosomal dominant Wolfram-like syndrome (PMID: 31521625); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 189251). For these reasons, this variant has been classified as Pathogenic.

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Wolfram syndrome 1

Pathogenic:3

May 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: WFS1 c.124C>T (p.Arg42X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.3e-05 in 194514 control chromosomes (i.e., 18 heterozygous carriers; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.124C>T has been reported in the literature in at least one compound heterozygous individual affected with atypical late-onset Wolfram syndrome 1 (WFS1) without diabetes insipidus (e.g., Rigoli_2022), suggesting the variant is likely to be associated with autosomal recessive WFS1. The variant was also found to segregate with a maturity-onset diabetes of the young phenotype in at least one family (e.g., Saint-Martin_2022). Additionally, c.124C>T has been reported in heterozygous individuals affected with early-onset diabetes (e.g., Huopio_2016), chronic progressive external ophthalmoplegia (e.g., Heighton_2019), and intellectual and psychiatric disorders (e.g., Rigoli_2022, Valentino_2021), without strong evidence for causality. However, the variant was also identified in many healthy controls (e.g., Fawcett_2010, Billings_2022). These findings therefore do not allow conclusions about the association of the variant with autosomal-dominant Wolfram-like syndrome. 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: 30245029, 36208030, 20028947, 31521625, 31980526, 27167055, 35206658, 34556497, 34356170). Nine ClinVar submitters (evaluation after 2014) have cited the variant and all submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 5). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive WFS1.

Nov 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg42X variant in WFS1 has not been previously identified in individuals with Wolfram syndrome, but has been identified in 0.02% (1/8540) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs71530923). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a pathogenic interpretation. This nonsense variant leads to a premature termination codon at position 42, which is predicted to lead to a truncated or absent protein. Heterozygous carries of pathogenic WFS1 variants may be at risk for developing low frequency sensorineural hearing loss and/or diabetes mellitus (Ohata 1998, Sandhu 2007, Franks 2008). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs71530923 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained.

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

Pathogenic:2

Feb 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 08, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Type 2 diabetes mellitus

Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5.

Inborn genetic diseases

Pathogenic:1

Sep 30, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.124C>T (p.R42*) alteration, located in exon 2 (coding exon 1) of the WFS1 gene, consists of a C to T substitution at nucleotide position 124. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 42.This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and autosomal dominant WFS1-related low frequency sensorineural hearing loss; however, it would be expected to be causative of autosomal recessive WFS1-related Wolfram syndrome based on mechanism of disease. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (22/225882) total alleles studied. The highest observed frequency was 0.02% (17/97912) of European (non-Finnish) alleles. Based on the available evidence, this alteration is classified as likely pathogenic.

Wolfram-like syndrome;C4551693:Wolfram syndrome 1

Pathogenic:1

Mar 01, 2021

New York Genome Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.124C>T, p.Arg42Ter nonsense variant identified in WFS1 has been reported individuals with Wolfram syndrome [PMID:31980526], type 2 diabetes [PMID:20028947], and chronic progressive external ophthalmoplegia [PMID:31521625]. This variant is not reported in gnomAD v3 database, indicating this is a rare allele. This nonsense variant leads to a premature termination codon at position 42, which is predicted to lead to a truncated or absent protein. Heterozygous carries of pathogenic WFS1 variants may be at risk for developing low frequency sensorineural hearing loss and/or diabetes mellitus [PMID:18040659,17603484, 9856492]. Based on the available evidence, the variant c.124C>T, p.Arg42Ter in the WFS1 gene is classified as likely pathogenic.

WFS1-related disorder

Pathogenic:1

Aug 26, 2022

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The WFS1 c.124C>T variant is predicted to result in premature protein termination (p.Arg42*). This variant was reported in the heterozygous state in a patient with adult onset chronic progressive external ophthalmoplegia (Table S1, Heighton et al. 2019. PubMed ID: 31521625), in a study of patients with type 2 diabetes (Appendix Table 5, Fawcett et al. 2009. PubMed ID: 20028947), and in a patient with intellectual disability and autism spectrum disorder (Valentino et al. 2021. PubMed ID: 34356170). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6279306-C-T). Nonsense variants in WFS1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Meniere disease

Uncertain:1

Jun 03, 2024

Center for Computational Biology & Bioinformatics, University of California, San Diego

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C4551693:Wolfram syndrome 1

Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.

Eigen

Benign

-0.031

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

0.59

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.83

GERP RS

2.4

PromoterAI

0.0026

Neutral

(source)

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over