rs111033240

Positions:

• chr7-107663331-C-G
• chr7-107663331-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP2

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 𝑓: 0.000010 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:1 B:5
• Conservation: PhyloP100: 0.651

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.200C>G	p.Thr67Ser	missense_variant	3/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.200C>G	p.Thr67Ser	missense_variant	3/21		NM_000441.2	P1
SLC26A4	ENST00000440056.1	c.200C>G	p.Thr67Ser	missense_variant	3/4	4

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

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

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:1 Uncertain:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	This variant is associated with the following publications: (PMID: 18250610, 24599119, 19040761, 19744334, 22796198, 17851929, 26969326, 30245029) -
Pathogenic, flagged submission	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Likely benign, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Mar 20, 2024	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). -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Nov 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 08, 2015	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. -

SLC26A4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2021

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;.
MutationTaster	Benign	1.0	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

Other links and lift over

dbSNP: rs111033240; hg19: chr7-107303776; COSMIC: COSV105848617; COSMIC: COSV105848617;