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]

x This classification has been retracted/unpublished!

Variant: NM_000441.2(SLC26A4):c.2145G>T (p.Lys715Asn)

Curation Version - 1.3
Curation History
JSON LD for Version 1.3

CA261425

43541 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b6f4c008-3e27-485a-bddb-183a7f974693

Approved on: 2019-11-26

Published on: 2023-09-18

HGVS expressions

NM_000441.2:c.2145G>T

NM_000441.2(SLC26A4):c.2145G>T (p.Lys715Asn)

NC_000007.14:g.107710109G>T

CM000669.2:g.107710109G>T

NC_000007.13:g.107350554G>T

CM000669.1:g.107350554G>T

NC_000007.12:g.107137790G>T

NG_008489.1:g.54475G>T

ENST00000644269.2:c.2145G>T

ENST00000644846.1:c.801G>T

ENST00000265715.7:c.2145G>T

ENST00000492030.2:n.377-46G>T

NM_000441.1:c.2145G>T

Uncertain Significance

PP4 PM3 PS3_Moderate

BS1 BP4

Evidence Links 2

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.2145G>T (p.Lys715Asn) variant in SLC26A4 has been identified in 0.06777% (95% CI of 29/30610) of South Asian chromosomes in gnomAD. The p.Lys715Asn variant has been observed in 2 probands with hearing loss in trans with another pathogenic or likely pathogenic variant (PM3; PMID: 26969326, LMM unpublished data SCV000060131.6). At least one proband with this variant presented with clinical features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4; LMM unpublished data SCV000060131.6). This variant has been observed in several other cases where a second variant in SLC26A4 was not found (PMID: 19509082, 19287372, 26188157). Functional studies including fluorescence assays and chloride exchange experiments have demonstrated that this variant impacts protein function (PS3_Moderate; PMID: 19509082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: PS3_Moderate, PM3, PP4.

PP4

2yo female with congenital SNHL and EVA. Het. for this variant as well as c.1229C>T (p.Thr410Met), classified as Pathogenic by VCEP (LMM internal data, SCV000060131.6)

PM3

LMM internal data: 2yo female with congenital sensorineural hearing loss and EVA. Heterozygous. Also het. for p.Thr410Met, classified as P by VCEP (0.5 PM3 points)

PubMed:26969326

PS3_Moderate

Fluorescence assay performed by Dai et al. 2009 indicates the K715N mutant exhibits decreased trafficking efficiency to the surface of Xenopus oocytes.

Fluorescence assay indicates the K715N mutant exhibits decreased trafficking efficiency to the surface of Xenopus oocytes. PubMed:19509082

BS1

v2: Present in 0.09474% (29/30610) of South Asian chromosomes. v3: Present in 0.1312% (4/3048) of South Asian chromosomes. Using v2, BS1_P is not met because the filtering allele frequency is only 0.06777%.

BP4

REVEL score 0.352. Conserved in UCSC database (no mammals have Asn at this site). Splicing is not predicted to be impacted in Alamut.

Curation History

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