Submissions for variant NM_000161.3(GCH1):c.631_632del (p.Met211fs)

dbSNP: rs886039379

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255238	SCV000321711	pathogenic	not provided	2016-06-21	criteria provided, single submitter	clinical testing	The c.631_632delAT variant in the GCH1 gene has been reported previously in multiple individuals with dopa-responsive dystonia (Furukawa et al., 1998; Bandmann et al., 1998; Clot et al., 2009; Sun et al., 2014). The c.631_632delAT variant causes a frameshift starting with codon Methionine 211, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Met211ValfsX38. This variant is predicted to cause loss of normal protein function through protein truncation. The c.631_632delAT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.631_632delAT as a pathogenic variant.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197727	SCV001368506	pathogenic	Dystonia 5	2018-10-29	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221402	SCV001393445	pathogenic	Dystonia 5; GTP cyclohydrolase I deficiency	2021-06-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in several individuals and families affected with dopa-responsive dystonia (PMID: 9778264, 19491146, 23430498). ClinVar contains an entry for this variant (Variation ID: 265173). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the GCH1 gene (p.Met211Valfs*38). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acids of the GCH1 protein.
Ambry Genetics	RCV001266568	SCV001444744	pathogenic	Inborn genetic diseases	2020-03-30	criteria provided, single submitter	clinical testing	The alteration results in a premature stop codon:_x000D_ _x000D_ The c.631_632delAT (p.M211Vfs*38) alteration, located in coding exon 6 of the GCH1 gene, results from a deletion of 2 nucleotides from position 631 to 632, causing a translational frameshift with a predicted alternate stop codon after 38 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of GCH1, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last 40 amino acids of the protein and the exact functional impact of these altered amino acids is unknown at this time. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GCH1 c.631_632delAT alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This variant has been reported previously in multiple individuals with dopa-responsive dystonia (Bandmann, 1998; Clot, 2009; Furukawa, 1998; Sun, 2014). Based on the available evidence, this alteration is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255238	SCV001446691	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255238	SCV002822137	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	GCH1: PVS1:Strong, PM2, PP4:Moderate, PS4:Moderate
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001197727	SCV004045948	pathogenic	Dystonia 5	2023-08-22	criteria provided, single submitter	clinical testing