ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.610G>A (p.Val204Ile)

gnomAD frequency: 0.00009  dbSNP: rs200891969
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000489411 SCV000230863 uncertain significance not provided 2014-11-11 criteria provided, single submitter clinical testing
GeneDx RCV000489411 SCV000576867 likely pathogenic not provided 2022-12-28 criteria provided, single submitter clinical testing Identified in the heterozygous state in individuals with dopa-responsive dystonia in whom no second variant was identified (Weissbach et al., 2015; Zech et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30911941, 25637381, 25525159, 20818608, 27666935, 19332422, 12874420, 30314816, 31213404, 24993959, 29484265, 32740907, 31996268, 35287262, 34670123, 26230973, 34999542, 34674384)
Invitae RCV000819611 SCV000960279 uncertain significance Dystonia 5; GTP cyclohydrolase I deficiency 2022-10-25 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 204 of the GCH1 protein (p.Val204Ile). This variant is present in population databases (rs200891969, gnomAD 0.1%). This missense change has been observed in individual(s) with dopa-responsive dystonia and/or guanine triphosphate cyclohydrolase type I deficiency without hyperphenylalaninemia (PMID: 12874420, 19332422, 20818608, 24993959, 27666935, 30911941). ClinVar contains an entry for this variant (Variation ID: 161248). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCH1 protein function. 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.
CeGaT Center for Human Genetics Tuebingen RCV000489411 SCV001149215 likely pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001705951 SCV001934376 likely pathogenic Dystonia 5 2023-07-18 criteria provided, single submitter clinical testing Criteria applied: PM3_STR,PM1,PM2_SUP,PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797636 SCV002041499 uncertain significance not specified 2021-11-27 criteria provided, single submitter clinical testing Variant summary: GCH1 c.610G>A (p.Val204Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251266 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GCH1 causing GTP Cyclohydrolase I Deficiency (0.00022 vs 0.0011), allowing no conclusion about variant significance. c.610G>A has been reported in the literature as compound heterozygote DOPA naive dystonia with normal serum prolactin levels (example, Furukawa_2003), early infantile onset autosomal recessive GTP Cyclohydrolase I Deficiency without Hyperphenylalaninemia (example, Opaladen_2011), DOPA responsive dystonia in compound heterozygosity where the other variant explained the phenotype and asymptomatic heterozygous family members (example, Menacci_2014, Giri_2019), generalized dystonia non responsive to DOPA (example, Beom Ahn_2019, Zech_2017). These report(s) do not provide unequivocal conclusions about association of the variant with GTP Cyclohydrolase I Deficiency and/or responsiveness to DOPA. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic, n=2; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV001705951 SCV003835716 uncertain significance Dystonia 5 2022-11-22 criteria provided, single submitter clinical testing
Lifecell International Pvt. Ltd RCV001705951 SCV003925696 likely pathogenic Dystonia 5 criteria provided, single submitter clinical testing A Heterozygous Missense variant c.610G>A in Exon 5 of the GCH1 gene that results in the amino acid substitution p.Val204Ile was identified. The observed variant has a maximum allele frequency of 0.00022/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as (Likely Pathogenic/Uncertain Significance) Conflicting Interpretations [Variation ID: 161248]. The observed variation has been previously reported in patients affected with Early-Onset Generalized Dystonia (Zech M, et.al., 2017). For these reasons, this variant has been classified as Likely Pathogenic.
CSER _CC_NCGL, University of Washington RCV000148506 SCV000190217 uncertain significance Dopa-responsive dystonia 2014-06-01 no assertion criteria provided research

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