NM_000441.2(SLC26A4):c.269C>T (p.Ser90Leu) AND Pendred syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000169192.3

Allele description [Variation Report for NM_000441.2(SLC26A4):c.269C>T (p.Ser90Leu)]

NM_000441.2(SLC26A4):c.269C>T (p.Ser90Leu)

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.269C>T (p.Ser90Leu)

HGVS:

NC_000007.14:g.107663400C>T
NG_008489.1:g.7766C>T
NM_000441.2:c.269C>TMANE SELECT
NP_000432.1:p.Ser90Leu
NC_000007.13:g.107303845C>T
NM_000441.1:c.269C>T
O43511:p.Ser90Leu

Protein change:

S90L

Links:

UniProtKB: O43511#VAR_021642; dbSNP: rs370588279

NCBI 1000 Genomes Browser:

rs370588279

Molecular consequence:

NM_000441.2:c.269C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Condition(s)

Name:: Pendred syndrome (PDS)
Synonyms:: DEAFNESS WITH GOITER; HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 2B; THYROID DYSHORMONOGENESIS 2B; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010134; MedGen: C0271829; Orphanet: 705; OMIM: 274600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220439	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jun 20, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 19287372, 12676893, 20842945, 17443271 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV005185150	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 21, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23555729, 26969326, 31599023, 19287372, 27792752, 31107121, 32417962 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000220439

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Jun 20, 2014)

unknown

literature only

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV005185150

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 21, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness.

Park HJ, Shaukat S, Liu XZ, Hahn SH, Naz S, Ghosh M, Kim HN, Moon SK, Abe S, Tukamoto K, Riazuddin S, Kabra M, Erdenetungalag R, Radnaabazar J, Khan S, Pandya A, Usami SI, Nance WE, Wilcox ER, Riazuddin S, Griffith AJ.

J Med Genet. 2003 Apr;40(4):242-8.

PubMed [citation]

PMID:: 12676893
PMCID:: PMC1735432

[An investigation of SLC26A4 gene mutation in nonsydromic hearing impairment in Hunan province of China].

Jiang L, Feng Y, Chen H, He C, Mei L.

Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2010 Jul;24(13):587-91. Chinese.

PubMed [citation]

PMID:: 20842945

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000220439.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005185150.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: SLC26A4 c.269C>T (p.Ser90Leu) 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 251466 control chromosomes. c.269C>T has been reported in the literature in the presumed compound heterozygous and homozygous states in multiple individuals affected with autosomal recessive nonsyndromic deafness and/or Pendred Syndrome (example, Gao_2016, Dahl_2013, Sloan-Heggen_2016, Zhang_2019, Chandru_2020, Anwar_2009) and has been suggested to be a founder mutation (example, Anwar_2009). These data indicate that the variant is very likely to be associated with disease. Functional analysis in vitro found this variant results in severely decreased transport activity and cellular mislocalization (example, Wasano_2020). The following publications have been ascertained in the context of this evaluation (PMID: 19287372, 32417962, 23555729, 27792752, 26969326, 31599023, 31107121). ClinVar contains an entry for this variant (Variation ID: 188842). Based on the evidence outlined above, the variant was classified 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: Sep 29, 2024

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