ClinVar Miner

Submissions for variant NM_033453.4(ITPA):c.532C>T (p.Arg178Cys)

gnomAD frequency: 0.00001  dbSNP: rs746930990
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001204840 SCV001376066 uncertain significance Inosine triphosphatase deficiency 2022-07-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 178 of the ITPA protein (p.Arg178Cys). 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 missense change has been observed in individual(s) with early infantile encephalopathy (PMID: 26224535). ClinVar contains an entry for this variant (Variation ID: 218090). 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 disruptive. Experimental studies have shown that this missense change affects ITPA function (PMID: 32129147). 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.
GeneDx RCV002277556 SCV002567641 pathogenic not provided 2022-02-17 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as R178C significantly reduces ITPA activity (Houndonougbo et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34645488, 27770805, 26224535, Zamzami2022[Review], 23770441, 34989426, 32129147)
PreventionGenetics, part of Exact Sciences RCV003407715 SCV004112638 pathogenic ITPA-related condition 2023-07-20 criteria provided, single submitter clinical testing The ITPA c.532C>T variant is predicted to result in the amino acid substitution p.Arg178Cys. This variant has been reported to be pathogenic for early infantile encephalopathy due to severely reduced inosine triphosphate pyrophosphatase (ITPase) activity (Kevelam et al. 2015. PubMed ID: 26224535; Shamseldin et al. 2021. PubMed ID: 34645488, Supplementary table S1). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-3204055-C-T). This variant is interpreted as pathogenic.
OMIM RCV000202320 SCV000257322 pathogenic Developmental and epileptic encephalopathy, 35 2015-10-01 no assertion criteria provided literature only

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