Submissions for variant NM_000161.3(GCH1):c.662T>C (p.Met221Thr)

gnomAD frequency: 0.00002  dbSNP: rs104894434

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260617	SCV001437709	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851776	SCV002262832	uncertain significance	Dystonia 5; GTP cyclohydrolase I deficiency	2022-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the GCH1 protein (p.Met221Thr). This variant is present in population databases (rs104894434, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of GCH1-related conditions (PMID: 9667588, 30314816). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 9281). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223756	SCV002502661	uncertain significance	not provided	2022-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004766995	SCV005380407	uncertain significance	not specified	2024-08-22	criteria provided, single submitter	clinical testing	Variant summary: GCH1 c.662T>C (p.Met221Thr) results in a non-conservative amino acid change located in the GTP cyclohydrolase I domain (IPR020602) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248966 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.662T>C has been reported in the literature in an individual affected with Dystonia (Furukawa_1998). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 9667588). ClinVar contains an entry for this variant (Variation ID: 9281). Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786251	SCV005397986	uncertain significance	Dystonia 5	2024-09-23	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dystonia, DOPA-responsive (MIM#128230) and hyperphenylalaninaemia, BH4-deficient, B (MIM#233910). Missense variants have been proven to have both a loss of function and dominant negative effect on protein function, causing both dominant and recessive forms of dystonia. Only loss of function variants have been reported for hyperphenylalaninaemia (PMID: 11026444,17111153). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM, PMID: 33713342). (I) 0112 - The dominant dystonia condition associated with this gene has incomplete penetrance (PMID: 11359069). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 33713342). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to threonine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (5 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated GTP cyclohydrolase I domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Met221Val) has been submitted to ClinVar once as a VUS. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been submitted to ClinVar once as pathogenic and twice as a VUS. This variant has also been identified once in a heterozygous individual with Parkinson's disease and classified as pathogenic (PMID: 30314816), and in a compound heterozygous state in an individual with severe dystonia and developmental delay (PMID: 9667588, 9566389). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant was observed in an individual with severe dystonia and developmental delay and her unaffected father. This individual was also compound heterozygous for another GCH1 variant which segregated with DOPA-responsive dystonia in three affected members of her family, in whom this variant was not observed. However, the compound heterozygous proband was noted to be more severely affected and with earlier onset of symptoms (PMID: 9667588, 9566389). (I) 1010 - Functional evidence for this variant is inconclusive. Patient lymphoblasts from a compound heterozygous individual had reduced neopterin levels compared to controls. However, lymphoblasts from their father who is heterozygous for just this variant did not have reduced neopterin levels, while lymphoblasts from individuals with only the other variant did have reduced neopterin levels (PMID: 9566389). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV002508112	SCV000030084	pathogenic	Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive	1998-07-01	no assertion criteria provided	literature only