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_000441.1(SLC26A4):c.1614C>T (p.Asn538=)

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CA132671

43517 (ClinVar)

Gene: SLC26A4

Condition: Pendred syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7a7216ba-1562-48ee-a59d-37f05afa50af

Approved on: 2019-07-29

Published on: 2019-10-02

HGVS expressions

NM_000441.1:c.1614C>T

NM_000441.1(SLC26A4):c.1614C>T (p.Asn538=)

NC_000007.14:g.107698111C>T

CM000669.2:g.107698111C>T

NC_000007.13:g.107338556C>T

CM000669.1:g.107338556C>T

NC_000007.12:g.107125792C>T

NG_008489.1:g.42477C>T

ENST00000265715.7:c.1614C>T

ENST00000477350.5:n.461C>T

ENST00000480841.5:n.463C>T

Likely Benign

BS1_Supporting BP4 BP7

PP4 PM1 PM3

Evidence Links 1

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The SLC26A4 p.Asn538Asn variant has been reported in the heterozygous state in one individual with unilateral hearing loss (PMID: 20621367). However, this variant is synonymous and is not predicted by computational prediction analysis, using MaxEntScan, to impact splicing (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 60/24964) of the p.Asn538Asn variant in SLC26A4 is 0.19168% for African chromosomes in gnomAD, 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; http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43517). 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, BP4, BP7.

BS1_Supporting

Present in 0.19168% (60/24964, 95% CI) of African alleles in gnomAD. -Agreed MD

BP4

Splicing does not appear to be impacted in Alamut. Agreed -MD

BP7

No impact to splicing is predicted. Two other mammals have a mutation at this codon. Agreed -MD

PP4

Patient had only unilateral hearing loss and was indicated by the authors to not have Pendred syndrome.

This paper looked at SCL26A4, FOXI1, KCNJ10 in 25 patients with unilateral hearing loss and ipsilateral EVA. The authors predicted the variant to impact splicing based on ESEfinder. PubMed:20621367

PM1

No hot spots in this gene.

PM3

Although one individual was identified in with the variant (Jonard 2010), this individual was heterozygous and did not harbor a second variant.

25 individuals with unilateral hearing loss and ipsilateral EVA were tested for variants in SLC26A4, KCNJ10, and FOXI1. The p.Asn538Asn variant was identified in the heterozygous state in one individual with severe left unilateral hearing loss and EVA. A second variant in SLC26A4 was not identified. -MD PubMed:20621367

Curation History

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