rs111033348

chr7-107674326-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):c.578C>T(p.Thr193Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,148 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.53

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-107674326-C-T is Pathogenic according to our data. Variant chr7-107674326-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107674326-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.578C>T	p.Thr193Ile	missense_variant	5/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.578C>T	p.Thr193Ile	missense_variant	5/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251446 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2023	Variant summary: SLC26A4 c.578C>T (p.Thr193Ile) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of 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 2e-05 in 251446 control chromosomes (gnomAD). c.578C>T has been reported in the literature in multiple individuals affected with Pendred Syndrome/Non-Syndromic Hearing Loss, including a family in which the variant was shown to segregate with disease (e.g. Adato_2000, Albert_2006, Tang_2015). Functional studies have shown the variant was undetectable in the plasma membrane, completely retained in the endoplasmic reticulum and showed no transport function (Moraes_2015, Wasano_2020). The following publications have been ascertained in the context of this evaluation (PMID: 10878664, 26752218, 25991456, 31599023, 16570074). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 17, 2018	- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3 Other:1

Likely pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Affects, no assertion criteria provided	in vitro;literature only	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 193 of the SLC26A4 protein (p.Thr193Ile). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 26752218, 31599023). 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 expected to disrupt SLC26A4 protein function. ClinVar contains an entry for this variant (Variation ID: 4830). This variant is also known as 801C>T. This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 10878664, 20597900, 26752218, 28964290). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs111033348, gnomAD 0.003%). -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2022

The p.Thr193Ile variant in SLC26A4 has been reported in at least 5 individuals with nonsyndromic hearing loss and enlarged vestibular aqueduct or Pendred syndrome in the homozygous or compound heterozygous state, and segregated with hearing loss in affected family members (Adato 2000 PMID: 1087866, Cengiz 2017 PMID: 28964290, Albert 2006 PMID: 16570074, Blons 2004 PMID: 15355436). It has also been identified in 0.001% (1/68018) of European chromosomes by gnomAD, v. 3 (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 4830). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies suggest the variant impairs protein localization and function (De Moraes PMID: 26752218, Wasano 2020 PMID: 31599023). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred Syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong,, PM2_Supporting, PP1, PP3, PS3_Supporting. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	0.99	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.93	P;P
Vest4		0.95
MutPred		0.84		Loss of catalytic residue at T193 (P = 0.0344);Loss of catalytic residue at T193 (P = 0.0344);
MVP		0.98
MPC		0.045
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.72
gMVP		0.94

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

Other links and lift over

dbSNP: rs111033348; hg19: chr7-107314771;