Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000441.2(SLC26A4):c.200C>G (p.Thr67Ser)

Curation Version - 1.1
Curation History
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CA132691

43531 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a2192ad9-6601-4289-bbb5-32f3b5814fd1

Approved on: 2024-03-20

Published on: 2024-04-01

HGVS expressions

NM_000441.2:c.200C>G

NM_000441.2(SLC26A4):c.200C>G

NM_000441.2(SLC26A4):c.200C>G (p.Thr67Ser)

NC_000007.14:g.107663331C>G

CM000669.2:g.107663331C>G

NC_000007.13:g.107303776C>G

CM000669.1:g.107303776C>G

NC_000007.12:g.107091012C>G

NG_008489.1:g.7697C>G

ENST00000644269.2:c.200C>G

ENST00000265715.7:c.200C>G

ENST00000440056.1:c.200C>G

NM_000441.1:c.200C>G

Likely Benign

BP2 BP4

PP4 PP1 PP3 PM2 PM3

Evidence Links 0

Expert Panel

Hearing Loss VCEP

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.200C>G (p.Thr67Ser) variant in SLC26A4 is a missense variant predicted to cause substitution of threonine by serine at amino acid 67. The highest population minor allele frequency in gnomAD v4.0.0 is 4/39700 alleles (0.0001008 or 0.01 %) in the East Asian population (PM2_supporting, BS1, and BA1 not met). The results from two predictors/lines of evidence, MaxEntScan and conservation analysis, with serine present at this residue in ten vertebrates, suggest that the variant does not impact SLC26A4 function (BP4). This variant has been observed in cis with the variant p.Leu236Val (c.706C>G) [PMIDs: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6], which is classified as likely pathogenic by the ClinGen Hearing Loss VCEP, in at least six affected individuals (BP2). The variant has been seen in the homozygous and compound heterozygous (in trans, phase confirmed) state in at least three other individuals affected with hearing loss (PMIDs: 18250610, 22796198, 26969326). However, PM3 was not applied due to the fact that these individuals may also have carried the p.Leu236Val variant that was causative of the disorder. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Pendred Syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BP4, BP2; Version 2; 3/20/24).

BP2

This variant has been observed in cis with p.Leu236Val (c.706C>G), which the Hearing Loss Expert Panel has classified as likely pathogenic, in at least 6 probands (BP2; PMID: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6).

BP4

The REVEL score 0.426, which does not meeting the hearing loss threshold of <0.15 for evidence of being benign. However, this residue is poorly conserved; serine is present at this residue in ten vertebrates (chimp, bushbaby, squirrel, naked mole rat, guinea pig, chinchilla, brush-tailed rat, opossum, Tasmanian devil, and the spotted gar). Also, the variant is not predicted to impact splicing.

PP4

Observed in one case of profound bilateral SNHL, EVA, multinodular goiter, and positive perchlorate test (PMID: 18250610). However, it was not clear whether this patient also carried the p.Leu236Val variant. The Hearing Loss Expert Panel believed that the evidence that this variant is likely benign outweighed this case.

PP1

Variant segregated with disease in one proband who had the c.919-2A>G mutation in trans (splicing mutation curated as pathogenic for autosomal recessive Pendred Syndrome by the Hearing Loss VCEP) (PMID: 18250610). However, it was not clear whether this patient also carried the p.Leu236Val variant. The Hearing Loss Expert Panel believed that the evidence that this variant is likely benign outweighed this case.

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

The highest population minor allele frequency in gnomAD v4.0.0 is 4/39700 alleles (0.0001008 or 0.01 %) in the East Asian population. Although this frequency is low enough to apply PM2_supporting, the ClinGen Hearing Loss Expert Panel believes that the evidence that this variant is likely benign outweighs the low allele frequency in population databases.

PM3

The variant has been seen in the homozygous or compound heterozygous in trans state in at least three other individuals affected with hearing loss (PMIDs: 18250610, 22796198, 26969326). However, PM3 was not applied due to the fact that these individuals may also have carried the p.Leu236Val variant that was causative of the disorder.

Curation History

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