rs398124234

Variant names:

• chr21-46145925-G-GC
• rs398124234
• NM_206965.2:c.990dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 16P and 5B. PVS1 PP5_Very_Strong BS1_Supporting BS2

The NM_206965.2(FTCD):​c.990dupG​(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:18 U:1 O:1
• Conservation: PhyloP100: 0.00200
• Publications: 13 publications found

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]

FTCD Gene-Disease associations (from GenCC):

• formiminoglutamic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 4019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00372 (555/149212) while in subpopulation NFE AF = 0.00591 (396/67014). AF 95% confidence interval is 0.00543. There are 3 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTCD	NM_206965.2	c.990dupG	p.Pro331AlafsTer2	frameshift_variant	Exon 9 of 14	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2	c.990dupG	p.Pro331AlafsTer2	frameshift_variant	Exon 9 of 15		NP_001307341.1
FTCD	NM_006657.3	c.990dupG	p.Pro331AlafsTer2	frameshift_variant	Exon 9 of 15		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.990dupG	p.Pro331AlafsTer2	frameshift_variant	Exon 9 of 14	1	NM_206965.2	ENSP00000380854.3

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

GnomAD2 exomes AF: 0.00291 AC: 326 AN: 112050 AF XY: 0.00317

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 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

African (AFR) AF: 0.000715 AC: 20 AN: 27984

American (AMR) AF: 0.00147 AC: 49 AN: 33236

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 12 AN: 24104

East Asian (EAS) AF: 0.0000308 AC: 1 AN: 32496

South Asian (SAS) AF: 0.00225 AC: 172 AN: 76488

European-Finnish (FIN) AF: 0.0106 AC: 362 AN: 34018

Middle Eastern (MID) AF: 0.000705 AC: 3 AN: 4258

European-Non Finnish (NFE) AF: 0.00565 AC: 6028 AN: 1065982

Other (OTH) AF: 0.00388 AC: 219 AN: 56410

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

African (AFR) AF: 0.00101 AC: 41 AN: 40542

American (AMR) AF: 0.00159 AC: 24 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.000869 AC: 3 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4842

South Asian (SAS) AF: 0.00150 AC: 7 AN: 4652

European-Finnish (FIN) AF: 0.00763 AC: 79 AN: 10358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00591 AC: 396 AN: 67014

Other (OTH) AF: 0.00242 AC: 5 AN: 2064

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00335

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutamate formiminotransferase deficiency Pathogenic:10 Other:1

Aug 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 25, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: 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/. -

Mar 17, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2021

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in FTCD causing Glutamate Formiminotransferase Deficiency phenotype. 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). The following publications have been ascertained in the context of this evaluation (PMID: 30740726, 12815595). ClinVar contains an entry for this variant (Variation ID: 4019). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 27, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide duplication (dupG) at coding position 990 of the FTCD gene that results in an early termition codon 2 base pairs downstream of the frameshift and is predicted to result in a null allele due through either protein truncation or a loss of FTCD expression by nonsense mediated decay. This a previously reported pathogenic allele (ClinVar) that is also referred to as c.1033dup in the literature. This variant has been observed in the homozygous or compound heterozygous state in several individuals with elevated formiminoglutamate in the urine (PMID: 12815595, 29178637, 30740726, 30679813). This variant is present in control population datasets (gnomAD database, 465 of 141806 alleles or 0.3%). Given the evidence, we consider this variant to be pathogenic. ACMG Criteria: PP5, PS4, PVS1 -

May 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6 Uncertain:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 (PMID: 12815595); This variant is associated with the following publications: (PMID: 25689098, 29178637, 31980526, 34426522, 12815595) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FTCD: PVS1 -

Sep 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jun 17, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PM3 -

Aug 23, 2024

Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

FTCD-related disorder Pathogenic:1

Jul 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0020
Mutation Taster		=25/175	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398124234; hg19: chr21-47565839; COSMIC: COSV52425520; COSMIC: COSV52425520;