NM_000441.2:c.200C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP2

This summary comes from the ClinGen Evidence Repository: The c.200C>G (p.Thr67Ser) variant in SLC26A4 is a missense variant predicted to cause substitution of threonine by serine at amino acid 67. The highest population minor allele frequency in gnomAD v4.0.0 is 4/39700 alleles (0.0001008 or 0.01 %) in the East Asian population (PM2_supporting, BS1, and BA1 not met). The results from two predictors/lines of evidence, MaxEntScan and conservation analysis, with serine present at this residue in ten vertebrates, suggest that the variant does not impact SLC26A4 function (BP4). This variant has been observed in cis with the variant p.Leu236Val (c.706C>G) [PMIDs: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6], which is classified as likely pathogenic by the ClinGen Hearing Loss VCEP, in at least six affected individuals (BP2). The variant has been seen in the homozygous and compound heterozygous (in trans, phase confirmed) state in at least three other individuals affected with hearing loss (PMIDs: 18250610, 22796198, 26969326). However, PM3 was not applied due to the fact that these individuals may also have carried the p.Leu236Val variant that was causative of the disorder. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Pendred Syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BP4, BP2; Version 2; 3/20/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132691/MONDO:0010134/005

Frequency

Genomes: not found (cov: 32)
Exomes đť‘“: 0.000010 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

1
18

Clinical Significance

Likely benign reviewed by expert panel P:1U:1B:5

Conservation

PhyloP100: 0.651
Variant links:
Genes affected
SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP2
For more information check the summary or visit ClinGen Evidence Repository.
BP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC26A4NM_000441.2 linkc.200C>G p.Thr67Ser missense_variant Exon 3 of 21 ENST00000644269.2 NP_000432.1 O43511-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A4ENST00000644269.2 linkc.200C>G p.Thr67Ser missense_variant Exon 3 of 21 NM_000441.2 ENSP00000494017.1 O43511-1
SLC26A4ENST00000440056.1 linkc.200C>G p.Thr67Ser missense_variant Exon 3 of 4 4 ENSP00000394760.1 C9JQG1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251496
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Pathogenic:1Uncertain:1Benign:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:1Benign:1
Nov 25, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18250610, 24599119, 19040761, 19744334, 22796198, 17851929, 26969326, 30245029) -

Feb 20, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 67 of the SLC26A4 protein (p.Thr67Ser). This variant is present in population databases (rs111033240, gnomAD 0.01%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 18250610, 22796198, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43531). 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 SLC26A4 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Pendred syndrome Uncertain:1Benign:1
Mar 20, 2024
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation

The c.200C>G (p.Thr67Ser) variant in SLC26A4 is a missense variant predicted to cause substitution of threonine by serine at amino acid 67. The highest population minor allele frequency in gnomAD v4.0.0 is 4/39700 alleles (0.0001008 or 0.01 %) in the East Asian population (PM2_supporting, BS1, and BA1 not met). The results from two predictors/lines of evidence, MaxEntScan and conservation analysis, with serine present at this residue in ten vertebrates, suggest that the variant does not impact SLC26A4 function (BP4). This variant has been observed in cis with the variant p.Leu236Val (c.706C>G) [PMIDs: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6], which is classified as likely pathogenic by the ClinGen Hearing Loss VCEP, in at least six affected individuals (BP2). The variant has been seen in the homozygous and compound heterozygous (in trans, phase confirmed) state in at least three other individuals affected with hearing loss (PMIDs: 18250610, 22796198, 26969326). However, PM3 was not applied due to the fact that these individuals may also have carried the p.Leu236Val variant that was causative of the disorder. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Pendred Syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BP4, BP2; Version 2; 3/20/24). -

Dec 28, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:2
Nov 08, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Thr67Ser variant was found in cis with the p.Leu236Val variant, which was found in compound heterozygosity (with p.Thr99fs) in an Asian individual with h earing loss and bilateral temporal bone abnormalities and then segregated across five meioses to a distant relative where it was found in homozygosity in two si blings with congenital hearing loss and a paternal family history of hearing los s. Both variants are extremely rare (ExAC: p.Thr67Ser 1/11578 Latino and p.Leu2 36Val 4/11578 Latino ). This variant has been classified as likely benign given that it occurs at a poorly conserved residue with several mammals having a serin e at this position. -

Nov 03, 2020
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SLC26A4-related disorder Benign:1
Apr 16, 2021
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
0.42
DANN
Benign
0.56
DEOGEN2
Benign
0.071
T;T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.25
.;T;T
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.59
N;N;.
PrimateAI
Benign
0.31
T
PROVEAN
Benign
1.2
N;.;N
REVEL
Uncertain
0.43
Sift
Benign
1.0
T;.;T
Sift4G
Benign
1.0
T;.;T
Polyphen
0.0
B;B;.
Vest4
0.22
MutPred
0.77
Loss of ubiquitination at K66 (P = 0.0992);Loss of ubiquitination at K66 (P = 0.0992);Loss of ubiquitination at K66 (P = 0.0992);
MVP
0.75
MPC
0.011
ClinPred
0.020
T
GERP RS
2.2
Varity_R
0.030
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs111033240; hg19: chr7-107303776; COSMIC: COSV105848617; COSMIC: COSV105848617; API