rs28939086

chr7-107690220-A-Cchr7-107690220-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000441.2(SLC26A4):c.1246A>C(p.Thr416Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000218 in 1,602,814 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). Synonymous variant affecting the same amino acid position (i.e. T416T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:1 O:2
• Conservation: PhyloP100: 6.32

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 7-107690220-A-C is Pathogenic according to our data. Variant chr7-107690220-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4818.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=12, Uncertain_significance=1, not_provided=1}. Variant chr7-107690220-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1246A>C	p.Thr416Pro	missense_variant	10/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1246A>C	p.Thr416Pro	missense_variant	10/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 250802 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135518

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

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: 0.000389

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000221 AC: 320 AN: 1450680 Hom.: 0 Cov.: 28 AF XY: 0.000205 AC XY: 148 AN XY: 722506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74316

Gnomad4 AFR AF: 0.000169

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: 0.000323

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000622 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:16 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 18, 2019	NM_000441.1(SLC26A4):c.1246A>C(T416P) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 23336812, 9618166, 9618167, 12354788 and 18310264. Classification of NM_000441.1(SLC26A4):c.1246A>C(T416P) 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2023	Variant summary: SLC26A4 c.1246A>C (p.Thr416Pro) 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 0.0002 in 250802 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0002 vs 0.0035), allowing no conclusion about variant significance. c.1246A>C has been reported in the literature in multiple bi-allelic individuals affected with Pendred Syndrome (examples: Napiontek_2004 and Mey_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15531480, 31633822). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2022	Published functional studies demonstrate that presence of T416P is associated with decreased or absent pendrin-induced transport of chloride, iodide, and bicarbonate in Xenopus oocytes (Scott et al., 2000; Yoon et al., 2008); 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: 22975760, 24224479, 19017801, 9618167, 18283249, 20301640, 12354788, 31599023, 18310264, 15531480, 26969326, 28000701, 23336812, 29739340, 30240412, 27771369, 30484383, 24860705, 31827275, 31980526, 32488467, 34426522, 34171171, 32387678, Byun[article], 31589614, 33199029, 35114279, 33583874, 33827324, 10861298, 11317356, 9618166) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 416 of the SLC26A4 protein (p.Thr416Pro). This variant is present in population databases (rs28939086, gnomAD 0.04%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 9618166, 14679580, 24224479). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4818). 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: 10861298, 12354788, 18310264). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2021	- -

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

Uncertain significance, criteria provided, single submitter	research	Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	-	- -
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	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 03, 2018	A heterozygous missense variant, NM_000441.1(SLC26A4):c.1246A>C, has been identified in exon 10 of 21 of the SLC26A4 gene. The variant is predicted to result in a minor amino acid change from threonine to proline at position 416 of the protein (NP_000432.1(SLC26A4):p.(Thr416Pro)). The threonine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the sulfate transporter domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.02% (55 heterozygotes in 276514, 0 homozygotes). The variant has been previously described as pathogenic (ClinVar, HGMD, Deafness variation database) and has been shown to segregate in multiple families with Pendred syndrome (Clinvar, Van Heuwe, P. et al. (1998)). It is one of the most commonly reported SLC26A4 variants associated with hearing loss in Europeans. Additionally, functional analysis has shown that the altered pendrin fails to localise to the cell membrane and is retained in the intracellular region (Yoon, JS. et al. (2008)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 22, 2017

The p.Thr416Pro variant in SLC26A4 has been reported in at least 10 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aque ducts (EVA), all of whom were compound heterozygous, and segregated with disease in 3 affected relatives from 2 families (Campbell 2001, Ladsous 2014, LMM data) . It has been identified in 0.04% (48/126104) of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs289 39086). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a carrier frequency for recessive heari ng loss. Computational prediction tools and conservation analysis suggest that t he p.Thr416Pro variant may impact the protein. In summary, this variant meets cr iteria to be classified as pathogenic for Pendred syndrome or nonsyndromic heari ng loss in an autosomal recessive manner based on multiple biallelic occurrences in individuals with hearing loss and segregation in affected relatives. ACMG/AM P Criteria applied: PM3_VeryStrong; PP1_Moderate; PP3; PP4. -

SLC26A4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The SLC26A4 c.1246A>C (p.Thr416Pro) missense variant is a well-documented pathogenic variant accounting for at least 15% of disease alleles in individuals with a confirmed diagnosis of Pendred syndrome who are of northern European descent (Alasti et al. 2014). Across a selection of the available literature, the p.Thr416Pro variant has been identified in a homozygous state in four patients, in a compound heterozygous state in 45 patients and in a heterozygous state in five patients (Coyle et al. 1998; van Hauwe et al. 1998; Campbell et al, 2001; Napiontek et al. 2004; Rendtorff et al. 2013; Ladsous et al. 2014; Pique et al. 2014). The variant was absent from 346 control chromosomes but is reported at a frequency of 0.00035 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Thr416Pro variant protein is retained in the endoplasmic reticulum and does not reach the plasma membrane as wild type, and the variant protein showed almost complete loss of iodide transport capacity (Rotman-Pikielny et al. 2002; Yoon et al. 2008). Based on the evidence the p.Thr416Pro variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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	0.90
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.5	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.77
MVP		0.98
MPC		0.074
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.98
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

Other links and lift over

dbSNP: rs28939086; hg19: chr7-107330665;