NM_000441.2(SLC26A4):c.707T>C (p.Leu236Pro) AND SLC26A4-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 21, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004528073.3

Allele description [Variation Report for NM_000441.2(SLC26A4):c.707T>C (p.Leu236Pro)]

NM_000441.2(SLC26A4):c.707T>C (p.Leu236Pro)

Gene:

SLC26A4:solute carrier family 26 member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q22.3

Genomic location:

Preferred name:

NM_000441.2(SLC26A4):c.707T>C (p.Leu236Pro)

HGVS:

NC_000007.14:g.107675051T>C
NG_008489.1:g.19417T>C
NM_000441.2:c.707T>CMANE SELECT
NP_000432.1:p.Leu236Pro
NC_000007.13:g.107315496T>C
NM_000441.1:c.707T>C
O43511:p.Leu236Pro
c.707T>C

Protein change:

L236P; LEU236PRO

Links:

UniProtKB: O43511#VAR_007441; OMIM: 605646.0005; dbSNP: rs80338848

Molecular consequence:

NM_000441.2:c.707T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: SLC26A4-related disorder
Synonyms:: SLC26A4-related condition; SLC26A4-Related Disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916169	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Sep 21, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 28273078, 9618166, 9618167, 11317356, 18310264, 12354788, 20301640, 25999548 Citation Link,
SCV004766575	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Feb 15, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000916169

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Sep 21, 2018)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV004766575

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Feb 15, 2024)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Screening of deafness-causing DNA variants that are common in patients of European ancestry using a microarray-based approach.

Yan D, Xiang G, Chai X, Qing J, Shang H, Zou B, Mittal R, Shen J, Smith RJ, Fan YS, Blanton SH, Tekin M, Morton C, Xing W, Cheng J, Liu XZ.

PLoS One. 2017;12(3):e0169219. doi: 10.1371/journal.pone.0169219.

PubMed [citation]

PMID:: 28273078
PMCID:: PMC5342170

Two frequent missense mutations in Pendred syndrome.

Van Hauwe P, Everett LA, Coucke P, Scott DA, Kraft ML, Ris-Stalpers C, Bolder C, Otten B, de Vijlder JJ, Dietrich NL, Ramesh A, Srisailapathy SC, Parving A, Cremers CW, Willems PJ, Smith RJ, Green ED, Van Camp G.

Hum Mol Genet. 1998 Jul;7(7):1099-104.

PubMed [citation]

PMID:: 9618166

See all PubMed Citations (8)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916169.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV004766575.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 20, 2026

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