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.147C>G (p.Ser49Arg)

CA4432373

227949 (ClinVar)

Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 714cab10-9700-444a-be53-9f2758251da9
Approved on: 2025-07-16
Published on: 2025-09-23

HGVS expressions

NM_000441.2:c.147C>G
NM_000441.2(SLC26A4):c.147C>G (p.Ser49Arg)
NC_000007.14:g.107661788C>G
CM000669.2:g.107661788C>G
NC_000007.13:g.107302233C>G
CM000669.1:g.107302233C>G
NC_000007.12:g.107089469C>G
NG_008489.1:g.6154C>G
ENST00000644269.2:c.147C>G
ENST00000265715.7:c.147C>G
ENST00000440056.1:c.147C>G
NM_000441.1:c.147C>G
NR_028137.1:n.11G>C
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Likely Benign

Met criteria codes 3
BP4 BS1_Supporting BS3_Supporting
Not Met criteria codes 11
PS4 PS3 PS1 PP1 PP3 PM3 PM1 PM5 PM2 BS4 BS2

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 NM_000441.2(SLC26A4):c.147C>G (p.Ser49Arg) variant has been identified in a heterozygous state in two Chinese individuals with congenital non-syndromic hearing loss (PMID: 25149764). No information about segregation of the variant or whether it was in trans with another SLC26A4 variant was given. The filtering allele frequency of the c.147C>G variant in the SLC26A4 gene is 0.27% for East Asian chromosomes by gnomADv4 with 95% CI, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein and splice prediction analysis using MaxEntScan does not suggest an impact to splicing (BP4). Fluorescence HCO3−/Cl− and I−/Cl− antiport functional assay show no difference compared to wild type protein (PMID : 31599023 ; BS3_P). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1_Supporting, BS3_Supporting, BP4 (ClinGen Hearing Loss VCEP specifications version 2; 7/16/2025).
Met criteria codes
BP4
This variant has a REVEL score 0.108, no splicing imact predicted, nucleotide not conserved, but animo acid is moderately conserved.
BS1_Supporting
The filtering allele frequency of the p.Ser49Arg variant in the SLC26A4 gene is 0.27% for East Asian chromosomes by gnomADV4 (121/40978 with 95% CI).
BS3_Supporting
Fluorescence HCO3−/Cl− and I−/Cl− antiport functional assay show no difference compared to wild type protein.

Not Met criteria codes
PS4
Case-control analysis was not performed. This variant has a higher MAF in the East Asian population (gnomAD).
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
The current variant is the only variant found in this codon in ClinVar.
PP1
No segregation was performed.
PP3
REVEL score 0.108
PM3
The variant has been identified in a heterozygous state in two Chinese individuals with congenital non-syndromic hearing loss (PMID: 25149764). No information about segregation of the variant or whether it was in trans with another SLC26A4 variant was given.
PM1
Does not impact a protein domain.
PM5
The current variant is the only variant found in this codon in ClinVar.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No segregation was performed.
BS2
No homozygous individuals in gnomAD with this variant have been reported.
Curation History
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