NM_000441.2(SLC26A4):c.1204G>A (p.Val402Met) AND Pendred syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 19, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001171536.4

Allele description [Variation Report for NM_000441.2(SLC26A4):c.1204G>A (p.Val402Met)]

NM_000441.2(SLC26A4):c.1204G>A (p.Val402Met)

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.1204G>A (p.Val402Met)

HGVS:

NC_000007.14:g.107690178G>A
NG_008489.1:g.34544G>A
NM_000441.2:c.1204G>AMANE SELECT
NP_000432.1:p.Val402Met
NC_000007.13:g.107330623G>A
NM_000441.1:c.1204G>A
NM_000441.2(SLC26A4):c.1204G>AMANE SELECT
O43511:p.Val402Met
c.1204G>A

Protein change:

V402M

Links:

UniProtKB: O43511#VAR_058580; dbSNP: rs397516414

NCBI 1000 Genomes Browser:

rs397516414

Molecular consequence:

NM_000441.2:c.1204G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pendred syndrome (PDS)
Synonyms:: DEAFNESS WITH GOITER; GOITER-DEAFNESS SYNDROME; HYPOTHYROIDISM, CONGENITAL, DUE TO 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
SCV001334321	ClinGen Hearing Loss Variant Curation Expert Panel	reviewed by expert panel (ClinGen HL ACMG Specifications v1)	Pathogenic (Feb 19, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002079992	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Jul 26, 2021)	germline	clinical testing
SCV005422309	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 14, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19204907, 38474007 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001334321

ClinGen Hearing Loss Variant Curation Expert Panel

reviewed by expert panel

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Feb 19, 2020)

germline

curation

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

Citation Link,

SCV002079992

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Jul 26, 2021)

germline

clinical testing

SCV005422309

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Oct 14, 2024)

germline

clinical testing

PubMed (2)
[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, curation

Citations

PubMed

Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?

Choi BY, Stewart AK, Madeo AC, Pryor SP, Lenhard S, Kittles R, Eisenman D, Kim HJ, Niparko J, Thomsen J, Arnos KS, Nance WE, King KA, Zalewski CK, Brewer CC, Shawker T, Reynolds JC, Butman JA, Karniski LP, Alper SL, Griffith AJ.

Hum Mutat. 2009 Apr;30(4):599-608. doi: 10.1002/humu.20884.

PubMed [citation]

PMID:: 19204907
PMCID:: PMC2663020

Functional Studies of Deafness-Associated Pendrin and Prestin Variants.

Takahashi S, Kojima T, Wasano K, Homma K.

Int J Mol Sci. 2024 Feb 27;25(5). doi: 10.3390/ijms25052759.

PubMed [citation]

PMID:: 38474007
PMCID:: PMC10931795

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV001334321.1

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

Description

The p.Val402Met variant in SLC26A4 was absent from gnomAD v2.1.1 and v3 (PM2). This variant has been detected in 2 probands with hearing loss. For both patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:19204907, Partners LMM unpublished data SCV000060082.6). The variant has been reported to segregate in one affected family member (PP1, PMID:19204907). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, LMM unpublished data SCV000060082.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:19204907). The REVEL computational prediction analysis tool produced a score of 0.77, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3_Strong, PM2, PP1, PP3, PP4, PS3_Supporting).

#	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 Natera, Inc., SCV002079992.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005422309.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: SLC26A4 c.1204G>A (p.Val402Met) results in a conservative amino acid change located in the SLC26A/SulP transporter domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250984 control chromosomes. c.1204G>A has been reported in the literature in two compound heterozygous siblings affected with hearing loss and enlargement of the vestibular aqueduct (e.g., Choi_2009). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g., Choi_2009, Takahashi_2024). The most pronounced variant effect results in <10% of normal anion transport function in a fluorometric antiport assay (e.g., Takahashi_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19204907, 38474007). ClinVar contains an entry for this variant (Variation ID: 43495). Based on the evidence outlined above, the variant was classified as likely 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: May 16, 2025

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