rs398124234

Positions:

• chr21-46145925-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_206965.2(FTCD):​c.990_991insG​(p.Pro331AlafsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 1,504,188 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 29)
  • Exomes 𝑓: 0.0051 (20 hom.)
• Consequence: FTCD NM_206965.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1 O:1
• Conservation: PhyloP100: 0.00200

Genes affected

FTCD (HGNC:3974): (formimidoyltransferase cyclodeaminase) The protein encoded by this gene is a bifunctional enzyme that channels 1-carbon units from formiminoglutamate, a metabolite of the histidine degradation pathway, to the folate pool. Mutations in this gene are associated with glutamate formiminotransferase deficiency. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-46145925-G-GC is Pathogenic according to our data. Variant chr21-46145925-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTCD	NM_206965.2	c.990_991insG	p.Pro331AlafsTer2	frameshift_variant	9/14	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2	c.990_991insG	p.Pro331AlafsTer2	frameshift_variant	9/15		NP_001307341.1
FTCD	NM_006657.3	c.990_991insG	p.Pro331AlafsTer2	frameshift_variant	9/15		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.990_991insG	p.Pro331AlafsTer2	frameshift_variant	9/14	1	NM_206965.2	ENSP00000380854	P1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 555 AN: 149106 Hom.: 3 Cov.: 29

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.000869

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.00245

GnomAD3 exomes AF: 0.00291 AC: 326 AN: 112050 Hom.: 2 AF XY: 0.00317 AC XY: 197 AN XY: 62226

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.000825

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00152

Gnomad FIN exome AF: 0.00914

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00507 AC: 6866 AN: 1354976 Hom.: 20 Cov.: 31 AF XY: 0.00493 AC XY: 3291 AN XY: 668200

Gnomad4 AFR exome AF: 0.000715

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.0000308

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00565

Gnomad4 OTH exome AF: 0.00388

GnomAD4 genome AF: 0.00372 AC: 555 AN: 149212 Hom.: 3 Cov.: 29 AF XY: 0.00368 AC XY: 268 AN XY: 72842

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00159

Gnomad4 ASJ AF: 0.000869

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00150

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.00591

Gnomad4 OTH AF: 0.00242

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00335

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutamate formiminotransferase deficiency Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 09, 2021	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. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2023	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. -

not provided Pathogenic:5 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	FTCD: PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2023	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 (PMID: 12815595); This variant is associated with the following publications: (PMID: 25689098, 29178637, 31980526, 34426522, 12815595) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	Aug 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Aug 18, 2022	PVS1, PS3, PM3 -
Uncertain significance, flagged submission	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 11, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2022

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. -

FTCD-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398124234; hg19: chr21-47565839;