ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.164+2T>C (rs397516420)

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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 RCV000036453 SCV000060108 pathogenic Rare genetic deafness 2012-03-26 criteria provided, single submitter clinical testing The 164+2T>C variant in SLC26A4 has not been reported in the literature. However , this variant has been previously identified by our laboratory in one individua l with hearing loss and EVA who had a second SLC26A4 variant. The 164+2T>C varia nt is predicted to cause abnormal splicing because the nucleotide substitution o ccurs in the invariant region of the splice consensus sequence. In summary, this variant meets our criteria to be classified as pathogenic.
GeneDx RCV000328168 SCV000330380 pathogenic not provided 2020-01-29 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26969326)
Invitae RCV000328168 SCV001578456 pathogenic not provided 2020-05-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the SLC26A4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. Disruption of this splice site has been observed in individual(s) with clinical features of Pendred Syndrome (PMID: 26969326, 29196752, 25724631). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS2+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 43518). 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 RCV000984221 SCV001132295 pathogenic Pendred syndrome 2019-07-12 no assertion criteria provided clinical testing
Natera, Inc. RCV000984221 SCV001455793 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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