ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1707+5G>A (rs192366176)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669310 SCV000794052 pathogenic Pendred syndrome 2017-09-07 criteria provided, single submitter clinical testing
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000515708 SCV000611820 pathogenic Enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000657917 SCV000779684 pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing The c.1707+5 G>A splice site variant in the SLC26A4 gene has been previously reported in both the homozygous and compound heterozygous state in association with SLC26A4-related disorders (Ganaha et al., 2013; Hao et al., 2018; Yang et al., 2005). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This pathogenic variant destroys the natural splice donor site in intron 15, and is expected to cause abnormal gene splicing. In summary, we consider this to be a pathogenic variant.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000515708 SCV000902357 pathogenic Enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control
Invitae RCV000657917 SCV000964527 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs192366176, ExAC 0.02%). This variant has been observed in individuals affected with sensorineural hearing loss (PMID: 21961810, 23705809, 26763877). This variant is also known as IVS15+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 446457). Experimental studies have shown that this intronic change causes the loss of SLC26A4 expression (PMID: 23705809). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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