ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2145G>T (p.Lys715Asn) (rs397516427)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000675123 SCV001245156 uncertain significance Pendred syndrome 2019-11-26 reviewed by expert panel curation 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in 2 probands with hearing loss in trans with another pathogenic or likely pathogenic variant (PM3; PMID: 26969326, LMM unpublished data SCV000060131.6).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of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4; LMM unpublished data SCV000060131.6).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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036476 SCV000060131 likely pathogenic Rare genetic deafness 2012-03-22 criteria provided, single submitter clinical testing The Lys715Asn variant in SLC26A4 has been reported in a heterozygous state in th ree probands with hearing loss and was absent from 100 control samples (Dia 2009 , Anwar 2009). In addition, functional studies showed reduced Cl- anion exchange activity compared to the wild type (Dia 2009). Furthermore, the presence of thi s variant in combination with a pathogenic variant and in an individual with cli nical features of hearing loss and EVA, increases the likelihood that the Lys715 Asn variant is pathogenic. In summary, this variant is likely pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585409 SCV000693248 likely pathogenic not provided 2017-10-01 criteria provided, single submitter clinical testing
Counsyl RCV000675123 SCV000800691 uncertain significance Pendred syndrome 2018-04-10 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV000675123 SCV001571754 likely pathogenic Pendred syndrome 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Supporting, BP4_Supporting

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