ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.334A>G (p.Thr112Ala)

gnomAD frequency: 0.00001  dbSNP: rs199990434
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001110342 SCV001267766 uncertain significance GTP cyclohydrolase I deficiency 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001110343 SCV001267767 uncertain significance Dystonia 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV002556162 SCV003503345 uncertain significance Dystonia 5; GTP cyclohydrolase I deficiency 2021-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 112 of the GCH1 protein (p.Thr112Ala). This variant is present in population databases (rs199990434, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of GCH1-related conditions (PMID: 25150291). ClinVar contains an entry for this variant (Variation ID: 881376). 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. Experimental studies have shown that this missense change does not substantially affect GCH1 function (PMID: 25150291). 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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