rs80338848

chr7-107675051-T-C

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.707T>C(p.Leu236Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,613,988 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L236V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.54

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr7-107675050-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43565.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 7-107675051-T-C is Pathogenic according to our data. Variant chr7-107675051-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107675051-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.707T>C	p.Leu236Pro	missense_variant	6/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.707T>C	p.Leu236Pro	missense_variant	6/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152190 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

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: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000274 AC: 69 AN: 251476 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000487 AC: 712 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.000483 AC XY: 351 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

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: 0.000622

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152190 Hom.: 0 Cov.: 30 AF XY: 0.000242 AC XY: 18 AN XY: 74354

Gnomad4 AFR AF: 0.000145

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: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000569 Hom.: 1

Bravo AF: 0.000276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SLC26A4 p.L236P variant has been reported in multiple homozygous or compound heterozygous individuals with hearing loss or hearing impairment (Yan_2017_PMID:28273078; Tang_2015_PMID:25991456; Pryor_2005_PMID:15689455; Pourova_2010_PMID:20597900; Busi_2012_PMID:22717225; Campbell_2001_PMID:11317356; Siem_2010_PMID:20553101; Van Hauwe_1998_PMID:9618166). The variant was identified in dbSNP (ID: rs80338848) and ClinVar (classified as pathogenic by Invitae, GeneDx, EGL Genetic Diagnostics and nine other submitters). The variant was identified in control databases in 83 of 282766 chromosomes (0 homozygous) at a frequency of 0.0002935, and was observed at the highest frequency in the European (non-Finnish) population in 77 of 129104 chromosomes (freq: 0.0005964) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.L236 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies have shown that this variant causes protein mislocalization and impaired iodide/chloride transport activity compared to wild type (Scott_2000_PMID:10861298, Rotman-Pikielny_2002_PMID:12354788, Yoon_2008_PMID:18310264). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2020	Published functional studies demonstrate a damaging effect due to improper intracellular localization of pendrin and loss of pendrin-induced iodide and chloride transport (Scott et al., 2000; Yoon et al., 2008); Common variant in Caucasian populations, accounting for approximately 10% of pathogenic alleles in published studies of Western European individuals (Tsukada et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22975760, 26969326, 11317356, 31827275, 12354788, 10861298, 18310264, 9618166, 26022370, 10700480, 20553101, 9618167, 22717225, 27771369, 31163360, 15689455, 20597900, 25999548, 31980526, 31589614) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the SLC26A4 protein (p.Leu236Pro). This variant is present in population databases (rs80338848, gnomAD 0.06%). This missense change has been observed in individual(s) with Pendred syndrome and hearing loss (PMID: 9618166, 15689455, 20553101, 20597900, 26969326). 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: 4817). 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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 03, 2019	- -

Pendred syndrome Pathogenic:6 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 22, 2018	- -
Likely 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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301640). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 83 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sulfate permease family (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants in individuals with European descent with Pendred syndrome or deafness 4 with enlarged vestibular aqueduct (ClinVar, PMID: 20301640). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000441.1(SLC26A4):c.707T>C(L236P) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 9618167, 9618166, 18310264 and 12354788. Classification of NM_000441.1(SLC26A4):c.707T>C(L236P) 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. -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 18, 2023	- -

SLC26A4-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 21, 2018	The SLC26A4 c.707T>C (p.Leu236Pro) missense variant is well described in the literature and is one of the three most common pathogenic variants in SLC26A4, which together account for 50% of the disease-causing alleles in probands with Pendred syndrome of northern European descent (Alasti et al. 2014; Tsukada et al. 2015). Across a selection of available literature, the p.Leu236Pro variant has been reported in at least four individuals in a homozygous state, 13 individuals in a compound heterozygous state, and one individual in a heterozygous state, all affected with Pendred syndrome (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001). The variant has also been reported in individuals affected with hearing loss, including two in a compound heterozygous state and five in a heterozygous state (Yan et al. 2017). Campbell et al. (2001) demonstrated segregation with disease in at least one multiplex family with temporal bone abnormalities. Haplotype analysis suggests a common founder effect for this variant (van Hauwe et al. 2008; Coyle et al. 1998). The p.Leu236Pro variant was absent from 257 control individuals (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001; Yan et al. 2017) and is reported at a frequency of 0.00105 in the European American population of the Exome Sequencing Project. Functional studies by Rotman-Pikielny et al. (2002) demonstrated that the variant protein is retained in the endoplasmic reticulum (ER) whereas the wild type protein targets to the plasma membrane. Yoon et al. (2008) confirmed the initial localization of the p.Leu236Pro variant protein in the ER and showed that after time, the protein was concentrated at the centrosome. They further determined that Cl-/HCO3- ion exchange activity of the variant protein was notably decreased, and that the variant was not temperature sensitive. Based on collective evidence, the p.Leu236Pro 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. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 15, 2024	The SLC26A4 c.707T>C variant is predicted to result in the amino acid substitution p.Leu236Pro. This variant has been reported to be causative for Pendred syndrome (van Hauwe et al 1998. PubMed ID: 9618166; Campbell et al 2001. PubMed ID: 11317356; Pourová et al 2010. PubMed ID: 20597900). This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Hearing impairment Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM2_Supporting, BP4_Supporting -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2017

The p.Leu236Pro variant in SLC26A4 has been reported in at least 15 individuals with either nonsyndromic hearing loss or Pendred syndrome who were homozygous or compound heterozygous, and it segregated in 4 affected family members from 2 fa milies (Busi 2012, Pryor 2005, Pourova 2010, Siem 2010, Van Hauwe 1998, LMM data ). One in vitro functional analysis study suggests the variant may impact normal intracellular trafficking of the protein (Rotman-Pikielny 2002). The p.Leu236Pr o variant has been identified in 0.1% (78/126638) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 80338848). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on bi-allelic occurrences in multiple affected indi viduals, segregation studies, functional evidence, and low frequency in the gene ral population. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Sup porting. -

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	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.94
MVP		0.99
MPC		0.061
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.98

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: rs80338848; hg19: chr7-107315496;