ClinVar Miner

Submissions for variant NM_013432.5(TONSL):c.1480G>A (p.Glu494Lys)

gnomAD frequency: 0.00001  dbSNP: rs775551492
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000790531 SCV001137724 pathogenic Sponastrime dysplasia 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001869237 SCV002221529 uncertain significance not provided 2022-10-04 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 638065). This missense change has been observed in individual(s) with SPONASTRIME Dysplasia (PMID: 30773277). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 494 of the TONSL protein (p.Glu494Lys). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon.
OMIM RCV000790531 SCV000929863 pathogenic Sponastrime dysplasia 2019-07-24 no assertion criteria provided literature only
University of Washington Center for Mendelian Genomics, University of Washington RCV000790531 SCV001439032 likely pathogenic Sponastrime dysplasia no assertion criteria provided research

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