NM_000441.2(SLC26A4):c.1003T>C (p.Phe335Leu) AND SLC26A4-related disorder

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 25, 2022
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:: RCV002291265.12

Allele description [Variation Report for NM_000441.2(SLC26A4):c.1003T>C (p.Phe335Leu)]

NM_000441.2(SLC26A4):c.1003T>C (p.Phe335Leu)

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.1003T>C (p.Phe335Leu)

HGVS:

NC_000007.14:g.107689054T>C
NG_008489.1:g.33420T>C
NM_000441.2:c.1003T>CMANE SELECT
NP_000432.1:p.Phe335Leu
NC_000007.13:g.107329499T>C
NM_000441.1:c.1003T>C
NM_000441.2(SLC26A4):c.1003T>CMANE SELECT
O43511:p.Phe335Leu
c.1003T>C

Protein change:

F335L; PHE335LEU

Links:

UniProtKB: O43511#VAR_021656; OMIM: 605646.0031; dbSNP: rs111033212

NCBI 1000 Genomes Browser:

rs111033212

Molecular consequence:

NM_000441.2:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

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
SCV000916170	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Dec 13, 2018)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 23965030, 11317356, 16570074, 17309986, 17503324, 18285825, 19204907, 19426954, 20597900, 23336812 Citation Link,
SCV002583769	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000916170

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Likely pathogenic
(Dec 13, 2018)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV002583769

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 25, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in Pendred syndrome/enlarged vestibular aqueducts.

Landa P, Differ AM, Rajput K, Jenkins L, Bitner-Glindzicz M.

BMC Med Genet. 2013 Aug 21;14:85. doi: 10.1186/1471-2350-14-85.

PubMed [citation]

PMID:: 23965030
PMCID:: PMC3765178

Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations.

Campbell C, Cucci RA, Prasad S, Green GE, Edeal JB, Galer CE, Karniski LP, Sheffield VC, Smith RJ.

Hum Mutat. 2001 May;17(5):403-11.

PubMed [citation]

PMID:: 11317356

See all PubMed Citations (11)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916170.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The SLC26A4 c.1003T>C (p.Phe335Leu) missense variant has been identified in a compound heterozygous state in two siblings with SLC26A4-related disorders, and in a heterozygous state in at least 17 individuals in whom a second variant was not identified (Campbell et al. 2001; Albert et al. 2006; Madden et al. 2007; Yang et al. 2007; Pera et al. 2008; Choi et al. 2009; PourovÃ¡ et al. 2010; Landa et al. 2013; Rendtorff et al. 2013). The compound heterozygous siblings were described with clinical features of hearing loss and enlarged vestibular aqueduct (EVA), where one of the siblings had bilateral EVAs and the other sibling had unilateral EVA. Most of the heterozygous probands presented with hearing loss with EVA, and the p.Phe335Leu variant was first identified in these probands through single-gene analyses of SLC26A4. In many probands with SLC26A4-related disorders, a second disease-causing variant is not identified (Yang et al. 2009). Digenic inheritance of heterozygous variants in SLC26A4 and KCNJ10 in association with hearing loss has been reported, and the p.Phe335Leu variant has been reported in a heterozygous state in two probands who also carried a KCNJ10 variant in a heterozygous state (Yang et al. 2009; Landa et al. 2013). The p.Phe335Leu variant is reported at a frequency of 0.00307 in the South Asian population of 1000 Genomes. Functional studies showed that the SLC26A4 protein carrying the p.Phe335Leu variant traffics to the plasma membrane in a manner indistinguishable from wild type protein and has substantial residual activity, but has a reduced Clâˆ’/Iâˆ’ exchange rate constant (Choi et al. 2009). Based on the collective evidence, the p.Phe335Leu variant is classified as likely 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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002583769.1

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

Description

PS3_Supporting, PM3_Strong, PP1, PP3, PP4

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

Last Updated: Aug 25, 2024

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