7-107690203-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1229C>T(p.Thr410Met) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,611,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T410K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:1
• Conservation: PhyloP100: 4.03

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107690203-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 691512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 7-107690203-C-T is Pathogenic according to our data. Variant chr7-107690203-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 43498.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-107690203-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1229C>T	p.Thr410Met	missense_variant	10/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1229C>T	p.Thr410Met	missense_variant	10/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 250840 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1459536 Hom.: 1 Cov.: 29 AF XY: 0.000172 AC XY: 125 AN XY: 726190

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000871 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	Jul 01, 2017	- -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -
Affects, no assertion criteria provided	clinical testing;in vitro	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -

Pendred syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000441.1(SLC26A4):c.1229C>T(T410M) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 16283880, 15355436, 11919333, 24224479, 21961810, 11932316, 19786220 and 9618167. Classification of NM_000441.1(SLC26A4):c.1229C>T(T410M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 17, 2018	This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VeryStrong; PMID: 25372295, 23638949, 25468468, 24338212, 25394566, 19786220, 19017801, 27541434, 21366435, 17309986, 24007330, 24224479, 21961810, 2844304, 19509082, 15811013). The p.Thr410Met variant in SLC26A4 has been reported to segregate in an autosomal recessive pattern with hearing loss in at least 7 family members (PP1_Strong; PMID: 19017801, 9618167, 15811013). Computational prediction tools and conservation analysis suggest that the p.Thr410Met variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA or Mondini malformation (PP4; PMID: 15355436, 15811013). The allele frequency of the p.Thr410Met variant in the SLC26A4 gene is 0.062% (19/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PP1_S, PP3, PS3_P, PM2_P, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2021	Variant summary: SLC26A4 c.1229C>T (p.Thr410Met) 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 0.00018 in 250840 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00018 vs 0.0035), allowing no conclusion about variant significance. c.1229C>T has been widely reported in the literature in multiple individuals affected with Pendred Syndrome (example, Coyle_1998, Fugazzola_2002, Chen_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and one espert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2021	T410M accounted for 4% of the SLC26A4 variants identified in a cohort of Korean patients with hearing loss and enlarged vestibular aqueduct (Lee et al., 2014); Published functional studies demonstrate this variant results in reduced or absent surface expression of the protein and impairs anion exchange activity (Lee et al., 2014; Taylor et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16711435, 21961810, 24338212, 25266519, 19786220, 24224479, 23469187, 15747138, 25468468, 20842945, 26763877, 15811013, 19509082, 11919333, 24007330, 27771369, 30733538, 32165640, 17718863, 9618167, 16283880, 28444304, 28604962, 28964290, 29372807, 30622556, 30693673, 31035178, 30036422, 31599023, 30842343, 31914302, 31541171, 32417962, 30896630, 30275481, 11932316, 31589614, 32447495, 15905611, 32645618, 33597575) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 410 of the SLC26A4 protein (p.Thr410Met). This variant is present in population databases (rs111033220, gnomAD 0.06%). This missense change has been observed in individuals with clinical features of Pendred syndrome (PMID: 9618167, 11919333, 11932316, 24224479, 25468468). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43498). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316, 24007330). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SLC26A4: PM3:Very Strong, PM2, PP1:Moderate -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 22, 2012

The Thr410Met variant in SLC26A4 has been reported in over 34 individuals with h earing loss and was not identified in 1576 control chromosomes (Arellano 2005, D ai 2009, Hutchin 2005, Wang 2007). Many of these individuals were homozygous or compound heterozygous. This variant causes the protein to be retained in the en doplasmic reticulum instead of functioning normally at the plasma membrane, thus greatly reducing its sodium-iodide efflux action (Taylor 2002). In summary, thi s variant meets our criteria to be classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.96
MVP		1.0
MPC		0.076
ClinPred		0.58	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111033220; hg19: chr7-107330648; COSMIC: COSV55915451; COSMIC: COSV55915451;