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
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000441.2(SLC26A4):c.1924T>C (p.Ser642Pro)

CA132685

43527 (ClinVar)

Gene: SLC26A4
Condition: Pendred syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: e93aa465-29e0-4b62-8b3a-75f3ae31260e
Approved on: 2025-08-20
Published on: 2025-09-23

HGVS expressions

NM_000441.2:c.1924T>C
NM_000441.2(SLC26A4):c.1924T>C
NM_000441.2(SLC26A4):c.1924T>C (p.Ser642Pro)
NC_000007.14:g.107701947T>C
CM000669.2:g.107701947T>C
NC_000007.13:g.107342392T>C
CM000669.1:g.107342392T>C
NC_000007.12:g.107129628T>C
NG_008489.1:g.46313T>C
ENST00000644269.2:c.1924T>C
ENST00000644846.1:c.635T>C
ENST00000265715.7:c.1924T>C
ENST00000492030.2:n.211T>C
NM_000441.1:c.1924T>C
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Uncertain Significance

Met criteria codes 2
PP3 BS1
Not Met criteria codes 2
PP4 PM3

Evidence Links 0

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.1924T>C variant in SLC26A4 is a missense variant predicted to cause substitution of serine by proline at amino acid 642. The highest population minor allele frequency in gnomAD v4.1 is 0.004332 (260/60022 alleles) in the Admixed-American population, which is higher than the ClinGen HL VCEP threshold (>0.003]) for BS1, and therefore meets this criterion (BS1 met). The computational predictor REVEL gives a score of 0.724, which is above the threshold of 0.7, evidence that correlates with impact on SLC26A4 function. (PP3 met). This variant has been observed in the homozygous state in at least nine apparently healthy adults (GeneDx internal data, SCV001816539.1, Invitae internal data, SCV001113490.7). This variant has also been observed with two co-occurring pathogenic variants in SLC26A4 phase unknown, in one patient reported to have hearing loss and enlarged vestibular aqueduct (Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060117.6). However, given its high allele frequency in the population and unknown phase with the co-occurring variant, PM3 was not applied. In summary, this variant meets the criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1, PP3 (ClinGen Hearing Loss VCEP specifications version 2; 8/20/2025).
Met criteria codes
PP3
REVEL score is 0.724, which meets the cutoff for PP3. The amino acid is relatively conserved but rat, dolphin, manatee and some other fish species have an alanine at this position. There is no predicted impact on splicing.
BS1
The highest population minor allele frequency in gnomAD v2.1.1 is 0.005308 (188/35420 alleles) in Latio/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1)
Not Met criteria codes
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
This variant was found in one female individual with SNHL with EVA and she had another pathogenic variant in SLC26A4. given its high allele frequency in the population and unknown phase with the co-occurring variant, PM3 was not applied.
Curation History
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