ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2089+1G>A (rs727503430)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151908 SCV000200416 pathogenic Rare genetic deafness 2014-04-11 criteria provided, single submitter clinical testing The 2089+1G>A variant in SLC26A4 has been previously identified in two individua ls with Pendred syndrome and segregated with disease in an affected sibling of one of these individuals (Blons 2004, Banghova 2008). This variant was absent fr om large population studies. The variant occurs in the invariant region (+1/2) o f the 5? splice consensus sequence and is predicted to cause altered splicing le ading to an abnormal or absent protein. In summary, this variant meets our crite ria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
GeneDx RCV000492847 SCV000582142 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing The c.2089+1G>A variant in the SLC26A4 gene has been reported previously in the presence of another SLC26A4 variant, in individuals with Pendred syndrome, exhibiting sensorineural hearing loss, vestibular aqueductal enlargement and both with and without thyroid involvement (Blons et al., 2004; Banghova et al., 2008; Ladsous et al., 2014). This splice site variant destroys the canonical splice donor site in intron 18. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2089+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2089+1G>A as a pathogenic variant.
Invitae RCV000492847 SCV000944137 pathogenic not provided 2020-06-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 18 of the SLC26A4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs727503430, ExAC 0.02%). This variant has been observed in multiple individuals with Pendred syndrome (PMID: 15355436, 2422447). ClinVar contains an entry for this variant (Variation ID: 165263). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000411928 SCV000485725 likely pathogenic Pendred syndrome 2016-02-02 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477837 SCV000536772 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2015-09-25 no assertion criteria provided research

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