4-6301615-C-T

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

8
9
2

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]

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
WFS1NM_006005.3 linkc.1820C>T p.Pro607Leu missense_variant Exon 8 of 8 ENST00000226760.5 NP_005996.2 O76024A0A0S2Z4V6
WFS1NM_001145853.1 linkc.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
WFS1ENST00000226760.5 linkc.1820C>T p.Pro607Leu missense_variant Exon 8 of 8 1 NM_006005.3 ENSP00000226760.1 O76024

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152200
Hom.:
0
Cov.:
34
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:
16
AN:
251406
Hom.:
0
AF XY:
0.0000662
AC XY:
9
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:
23
AN:
1461800
Hom.:
0
Cov.:
99
AF XY:
0.0000110
AC XY:
8
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:
11
AN:
152318
Hom.:
0
Cov.:
34
AF XY:
0.0000806
AC XY:
6
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:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000659
AC:
8

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
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
.;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Uncertain
2.6
M;M
PrimateAI
Uncertain
0.54
T
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
D
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.

Other links and lift over

dbSNP: rs373862003; hg19: chr4-6303342; API