ClinVar Miner

Submissions for variant NM_000161.2(GCH1):c.671A>G (p.Lys224Arg) (rs41298442)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517539 SCV000613388 likely pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000009865 SCV000883144 pathogenic Dystonia 5, Dopa-responsive type 2018-11-21 criteria provided, single submitter clinical testing
Invitae RCV000525589 SCV000631821 uncertain significance Dystonia 5, Dopa-responsive type; GTP cyclohydrolase I deficiency 2018-01-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 224 of the GCH1 protein (p.Lys224Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs41298442, ExAC 0.1%). This variant has been reported as heterozygous or compound heterozygous with a second, rare GCH1 variant, in individuals and families affected with dopa responsive dystonia (PMID: 8852666, 12391354, 17044972, 1530300, 19332422, 18044725, 9667588). It has also been reported in an individual affected with Parkinson's disease (PMID: 24993959, 25497597) and reported in unaffected individuals (PMID: 23430498). ClinVar contains an entry for this variant (Variation ID: 9283). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has been reported in affected and unaffected individuals, and occurs at a somewhat high frequency in the general population. This variant has uncertain impact on GCH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000009865 SCV000030086 pathogenic Dystonia 5, Dopa-responsive type 2002-10-22 no assertion criteria provided literature only
OMIM RCV000009866 SCV000030087 pathogenic Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive 2002-10-22 no assertion criteria provided literature only

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