NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr) AND Pendred syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jun 24, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000169232.3

Allele description [Variation Report for NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)]

NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)

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.554G>C (p.Arg185Thr)
Other names:
NM_000441.1(SLC26A4):c.554G>C(p.Arg185Thr)
HGVS:
  • NC_000007.14:g.107674302G>C
  • NG_008489.1:g.18668G>C
  • NM_000441.2:c.554G>CMANE SELECT
  • NP_000432.1:p.Arg185Thr
  • NC_000007.13:g.107314747G>C
  • NM_000441.1:c.554G>C
  • NM_000441.2(SLC26A4):c.554G>CMANE SELECT
  • O43511:p.Arg185Thr
Protein change:
R185T
Links:
UniProtKB: O43511#VAR_064991; dbSNP: rs542620119
NCBI 1000 Genomes Browser:
rs542620119
Molecular consequence:
  • NM_000441.2:c.554G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220501Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 10, 2014)
unknownliterature only

PubMed (3)
[See all records that cite these PMIDs]

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

Citation Link,

SCV001428425ClinGen Hearing Loss Variant Curation Expert Panelreviewed by expert panel
Likely pathogenic
(Jun 24, 2020)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001792214Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospitalcriteria provided, single submitter
Pathogenicgermlineresearch

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1yesresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Spectrum and frequency of SLC26A4 mutations among Czech patients with early hearing loss with and without Enlarged Vestibular Aqueduct (EVA).

Pourová R, Janousek P, Jurovcík M, Dvoráková M, Malíková M, Rasková D, Bendová O, Leonardi E, Murgia A, Kabelka Z, Astl J, Seeman P.

Ann Hum Genet. 2010 Jul;74(4):299-307. doi: 10.1111/j.1469-1809.2010.00581.x.

PubMed [citation]
PMID:
20597900

Use of SLC26A4 mutation testing for unilateral enlargement of the vestibular aqueduct.

Chattaraj P, Reimold FR, Muskett JA, Shmukler BE, Chien WW, Madeo AC, Pryor SP, Zalewski CK, Butman JA, Brewer CC, Kenna MA, Alper SL, Griffith AJ.

JAMA Otolaryngol Head Neck Surg. 2013 Sep;139(9):907-13. doi: 10.1001/jamaoto.2013.4185. Erratum in: JAMA Otolaryngol Head Neck Surg. 2014 Dec;140(12):1212.

PubMed [citation]
PMID:
24051746
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000220501.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV001428425.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The c.554G>A (p.Arg185Thr) variant in SLC26A4 was present in 0.03287% (1/3042) of South Asian alleles in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; gnomad.broadinstitute.org). This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as two probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650). It was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID: 22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3, PS3_Supporting, PM2_Supporting, PP3, PP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital, SCV001792214.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providedyesresearch PubMed (2)

Description

in compound heterozygosis with the c.412G>T variant in a subject with bilateral non-syndromic sensorineural prelingual hearing loss (sporadic)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not provideddiscovery1not providednot providednot provided

Last Updated: Oct 16, 2021

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