4-6301615-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_006005.3(WFS1):c.1820C>T(p.Pro607Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,118 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P607R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 6.97

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:

ENSG00000286176 (HGNC:):

ENSG00000286176 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301615-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1297726.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 4-6301615-C-T is Pathogenic according to our data. Variant chr4-6301615-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45441.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.1820C>T	p.Pro607Leu	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.1820C>T	p.Pro607Leu	missense_variant	Exon 8 of 8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.1820C>T	p.Pro607Leu	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251406

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Mar 14, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with hearing loss or congenital cataracts in published literature; patients were also heterozygous for WFS1 p.(R868H); it is unknown if the two variants are on the same allele (in cis) or on opposite alleles (in trans) (PMID: 36729443, 26969326, 36597107); 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: 26435059, 36729443, 36597107, 26969326, 37719678, 12707373) -

Jun 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 607 of the WFS1 protein (p.Pro607Leu). This variant is present in population databases (rs373862003, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of non-syndromic hearing loss (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 45441). 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) performed at Invitae indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 80%. This variant disrupts the p.Pro607 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707373). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:2

Sep 25, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: WFS1 c.1820C>T (p.Pro607Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251406 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WFS1 causing Wolfram Syndrome 1, allowing no conclusion about variant significance. c.1820C>T has been reported in the literature in several individuals undergoing multigene panel testing for hearing loss or inherited eye diseases (congenital cataracts), where it is frequently reported together with c.2603G>A (p.Arg868His), although phase has not been specified (e.g. Sloan-Heggen_2016, Li_2023, Ma_2023). These reports 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: 36729443, 36597107, 26969326). ClinVar contains an entry for this variant (Variation ID: 45441). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 09, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Pro607Leu variant in WFS1 has not been reported in affected individuals, but has been identified in 1/8600 European American chromosomes from a broad popula tion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. In summary, addit ional information is needed to fully assess the clinical significance of the Pro 607Leu variant. -

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

Pathogenic:1

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the heterozygous state with a second WFS1 variant in a patient with sporadic non-syndromic hearing loss (Sloan-Heggen, 2016)._x000D_ _x000D_ Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Monogenic diabetes

Uncertain:1

Sep 28, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: PP3 (0.846 + 9 predictors), PM2_supporting (based on ClinGen HL approved rules 9/28/18, says can use PM2 as supporting if MAF is <0.007% and MAF of c.1820C>T in gnomAD is 0.0069%)= VUS Note: in PMID 26969326, variant ID'd in patient with sporadic NSHL, in trans with other WFS1 variant (c.2603G>A p.R868H; has REVEL score of 0.877/PP3, can use PM2-supporting, also VUS) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.85

Sift

Benign

0.040

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

1.0

ClinPred

0.58

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.95

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