ClinVar Miner

Submissions for variant NM_138459.5(NUS1):c.119G>A (p.Cys40Tyr)

gnomAD frequency: 0.00001  dbSNP: rs759672395
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV002510754 SCV002820318 uncertain significance Intellectual disability, autosomal dominant 55, with seizures criteria provided, single submitter clinical testing The missense variant p.C40Y in NUS1 (NM_138459.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. Although the variant is present at 0.0031% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.C40Y variant is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between cysteine and tyrosine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico tools predict contradictory effects (SIFT-Tolerated, Polyphen-2- Damaging) and the residue is conserved across species. For these reasons, this variant has been classified as Uncertain Significance
Labcorp Genetics (formerly Invitae), Labcorp RCV002571604 SCV003466027 uncertain significance Congenital disorder of glycosylation, type IAA 2024-10-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 40 of the NUS1 protein (p.Cys40Tyr). This variant is present in population databases (rs759672395, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 36801247). ClinVar contains an entry for this variant (Variation ID: 1878663). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

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