Submissions for variant NM_206965.2(FTCD):c.990dup (p.Pro331fs)

dbSNP: rs398124234

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081452	SCV000233112	pathogenic	not provided	2016-06-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004234	SCV000245484	pathogenic	Glutamate formiminotransferase deficiency	2022-03-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000081452	SCV000568833	pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing	Functional studies show a truncated protein, loss of the cyclodeaminase domain, but normal formiminotransferase activity; study authors suggest second step in reaction is hindered despite intact formiminotransferase activity (Hilton et al., 2003); This variant is associated with the following publications: (PMID: 12815595, 25689098, 29178637, 31980526, 34426522)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000081452	SCV000610959	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing
Invitae	RCV000004234	SCV000826419	likely pathogenic	Glutamate formiminotransferase deficiency	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro331Alafs*2) in the FTCD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FTCD are known to be pathogenic (PMID: 29178637, 30740726). This variant is present in population databases (rs398124234, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with glutamate formiminotransferase deficiency (PMID: 12815595, 29178637, 30740726). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4019). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000004234	SCV002023766	pathogenic	Glutamate formiminotransferase deficiency	2023-10-25	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000004234	SCV002503860	pathogenic	Glutamate formiminotransferase deficiency	2021-04-09	criteria provided, single submitter	clinical testing	This sequence change is a duplication of 1 bp in exon 9 (of 14) of FTCD that is predicted to create a premature termination codon at position 332 (p.(Pro331Alafs*2)). It is expected to result in nonsense mediated decay, in a gene where loss of function is an established mechanism of disease (ClinGen). The variant is present in a large population cohort at a frequency of 0.3% (rs398124234, 465/141,806 alleles, 3 homozygotes in gnomAD v2.1). It has been identified in the homozygous and the compound heterozygous state in multiple individuals with formimidoyltransferase cyclodeaminase deficiency with elevated levels of formiminoglutamate (FIGLU) in the urine or blood (PMID: 12815595, 26633545, 29178637, 30740726). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as PATHOGENIC . Following criteria are met: PVS1, PM3_VeryStrong, PP4, BS1.
Mendelics	RCV000004234	SCV002516406	pathogenic	Glutamate formiminotransferase deficiency	2022-05-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000081452	SCV002585909	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	FTCD: PVS1
Ambry Genetics	RCV002512745	SCV003749669	pathogenic	Inborn genetic diseases	2022-03-09	criteria provided, single submitter	clinical testing	The c.990dupG (p.P331Afs*2) alteration, located in exon 9 (coding exon 9) of the FTCD gene, consists of a duplication of G at position 990, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the homozygous and compound heterozygous state with a second FTCD alteration in patients with glutamate formiminotransferase deficiency (Ahrens-Nicklas, 2019; Hilton, 2003; Majumdar, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000081452	SCV004026481	pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	PVS1, PS3, PM3
PreventionGenetics, part of Exact Sciences	RCV003390640	SCV004112641	pathogenic	FTCD-related condition	2023-05-19	criteria provided, single submitter	clinical testing	The FTCD c.990dupG variant is predicted to result in a frameshift and premature protein termination (p.Pro331Alafs*2). This variant has been reported in the homozygous state or in the heterozygous state with a second pathogenic variant in patients with autosomal recessive glutamate formiminotransferase deficiency. The reported FTCD variants were confirmed to be compound heterozygous in at least one reported family (e.g., Majumdar et al. 2017. PubMed ID: 29178637). The c.990dup variant introduces a premature stop codon between the enzyme formiminotransferase and cyclodeaminase domains. This variant has been reported to lead to a truncated FTCD enzyme missing the cyclodeaminase domain (Hilton et al. 2003. PubMed ID: 12815595, reported as c.1033insG). Additional predicted FTCD loss-of-function variants have been reported in association with formiminoglutamic aciduria (Human Gene Mutation Database; https://www.hgmd.cf.ac.uk/). Several outside laboratories have classified this variant as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/4019/). Taken together, we classify this variant as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004234	SCV004122875	pathogenic	Glutamate formiminotransferase deficiency	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: FTCD c.990dupG (p.Pro331AlafsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0029 in 112050 control chromosomes in the gnomAD database, including 2 homozygotes. c.990dupG (also known as c.1033insG) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Glutamate Formiminotransferase Deficiency (example: Hilton_2003, Ahrens-Nicklas_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that the variant results in a truncated protein and loss of the cyclodeaminase domain (Hilton_2003). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classfied the variant as pathogenic/likely pathogenic (n=10) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004234	SCV000024400	pathogenic	Glutamate formiminotransferase deficiency	2003-07-01	no assertion criteria provided	literature only
GenomeConnect - Brain Gene Registry	RCV000004234	SCV004801641	not provided	Glutamate formiminotransferase deficiency		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 09-23-2014 by Fulgent Diagnostics . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.