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.1708G>A (p.Val570Ile)

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CA132675

43521 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 24075c06-5af4-42e6-8a7e-ef7203a64602

Approved on: 2019-10-29

Published on: 2019-10-29

HGVS expressions

NM_000441.2:c.1708G>A

NM_000441.2(SLC26A4):c.1708G>A (p.Val570Ile)

NC_000007.14:g.107701101G>A

CM000669.2:g.107701101G>A

NC_000007.13:g.107341546G>A

CM000669.1:g.107341546G>A

NC_000007.12:g.107128782G>A

NG_008489.1:g.45467G>A

ENST00000644269.2:c.1708G>A

ENST00000644846.1:c.419G>A

ENST00000265715.7:c.1708G>A

ENST00000480841.5:n.557G>A

ENST00000492030.2:n.91-726G>A

NM_000441.1:c.1708G>A

Likely Pathogenic

PP3 PP4 PM3_Strong

BS1

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.1708G>A (p.Val570Ile) variant in SLC26A4 has been detected in 2 different patients with hearing loss and the variant was found in trans with the pathogenic variant p.Leu117Phe (PM3_Strong, LMM unpublished data SCV000060111.6). One of these individuals presented with sensorineural hearing loss with enlarged vestibular aqueducts (PP4, LMM unpublished data SCV000060111.6). While the REVEL score was 0.547, this variant is located at the first nucleotide of the exon and splice prediction analysis using MaxEntScan suggests an impact on splicing (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_Strong, PP4, PP3).

PP3

The nucleotide is heavily conserved (all 100 vertebrates in UCSC have Valine at this position) and splicing predictors (including MaxEntScan) predict the loss of the 3' consensus splice sequence.

PP4

A proband (LMM internal data) with the variant presented with SNHL with EVA which meets guidelines to be classified with PP4 according to the HLVCEP-specified guidelines. For details on the proband, please see the PM3 classification.

PM3_Strong

A 6 month old proband of Ashkenazi Jewish ancestry presented with congenital moderate mixed hearing loss. She was found to be a compound heterozygote for 2 variants in SLC26A4 (p.Val570Ile and p.Leu117Phe, which is classified as LP by the HL VCEP in ClinVar). The two variants were confirmed in trans by parental testing. This proband also had Heterozygous MYO15A: p.Ala2456Gly, POU3F4: p.Pro169Leu, EYA4: p.Gly473Val variants. This proband was scored with 1 point for PM3. (LMM Internal Data) A 20 year old proband of Ashkenazi jewish ancestry presented with profound SNHL with EVA and was found to have the same variants as the proband above also confirmed in trans by parental testing. This proband was also scored with 1 PM3 point. Total PM3 Points: 2 --> PM3_Strong

BS1

Variant present in 8/113438 (0.08%) of Ashekanazi Jewish chromosomes and the FAF (95%CI) is 0.0003956. Using the FAF with the 95% CI, this meets PM2_Supporting.

Curation History

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