The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)

CA274070

188878 (ClinVar)

Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: cfc9189b-83ef-4fee-9391-68daefe50667
Approved on: 2024-10-16
Published on: 2025-01-06

HGVS expressions

NM_000441.2(SLC26A4):c.554G>C
NM_000441.2:c.554G>C
NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)
NC_000007.14:g.107674302G>C
CM000669.2:g.107674302G>C
NC_000007.13:g.107314747G>C
CM000669.1:g.107314747G>C
NC_000007.12:g.107101983G>C
NG_008489.1:g.18668G>C
ENST00000644269.2:c.554G>C
ENST00000265715.7:c.554G>C
NM_000441.1:c.554G>C
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Likely Pathogenic

Met criteria codes 5
PS3_Supporting PP4 PP3 PM3 PM2_Supporting

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.554G>A variant in SLC26A4 is a missense variant predicted to cause substitution of arginine by threonine at amino acid 185 (p.Arg185Thr). The variant was present in 0.0165% (1/6062) of Middle Eastern alleles, which is the highest population minor allele frequency in gnomAD v4.1.0, and PM2_Supporting was applied at the recommendation of the expert panel. 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 in three probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650, 34680964). The variant was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Additionally, it was observed in one proband with hearing loss, enlarged vestibular aqueduct, and Mondini malformation who was compound heterozygous with a second pathogenic variant with phase unknown (PMID: 34599368). The variant was also seen in an infant with mild congenital bilateral sensorineural hearing loss who also had two pathogenic OTOG variants in trans (Invitae internal data ClinVar SCV002243689.3). 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: PM2_Supporting, PM3, PS3_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024)
Met criteria codes
PS3_Supporting
Fluorometric assay in COS-7 cells transfected with this variant demonstrated impaired chloride/iodide transport (PMID: 22285650).

PP4
1 proband with this variant had sporadic prelingual hearing loss, Mondini malformation, and EVA (PMID: 34599368)
PP3
The computational predictor REVEL gives a score of 0.876 which meets PP3 as the REVEL score is ≥ 0.7
PM3
1 PM3 point was assigned to a proband with unilateral hearing loss and EVA with the c.890delC (p.Pro297fs) variant in SLC26A4 in trans (PMID: 24051746). Additionally, 0.5 points were assigned to a proband with sporadic prelingual hearing loss, Mondini malformation, and EVA who was compound heterozygous with the pathogenic c.412G>T (p.Val138Phe) variant in SLC26A4 (PMID: 34599368).
PM2_Supporting
This variant has a minor allele frequency of 0.01650% (1/6062) in the Middle Eastern population, and PM2_Supporting was applied at the recommendation of the expert panel
Curation History
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