ClinVar Miner

Submissions for variant NM_206965.2(FTCD):c.1607T>A (p.Leu536Ter)

gnomAD frequency: 0.00116  dbSNP: rs149266909
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000174758 SCV000226123 pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731503 SCV001983611 uncertain significance not specified 2021-09-30 criteria provided, single submitter clinical testing Variant summary: FTCD c.1607T>A (p.Leu536X) results in a premature termination codon, which is predicted to remove the last five amino acids of the protein and keep the Cyclodeaminase domain intact (InterPro database). The variant allele was found at a frequency of 0.00029 in 247992 control chromosomes in the gnomAD database, including 1 homozygotes. c.1607T>A has been reported in the literature in multiple individuals affected with Glutamate Formiminotransferase Deficiency (Majumdar_2017, Ahrens-Nicklas_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic. However, at least one truncation variant upstream (c.1366dup/p.Glu456fs) has conflicting classification in ClinVar database. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001199935 SCV002240206 pathogenic Glutamate formiminotransferase deficiency 2023-11-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu536*) in the FTCD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the FTCD protein. This variant is present in population databases (rs149266909, gnomAD 0.4%). This premature translational stop signal has been observed in individuals with glutamate formiminotransferase deficiency (PMID: 29178637, 30740726). ClinVar contains an entry for this variant (Variation ID: 194395). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001199935 SCV004847483 likely pathogenic Glutamate formiminotransferase deficiency 2024-03-28 criteria provided, single submitter clinical testing The p.Leu536X variant in FTCD has been reported in 5 compound heterozygous and 1 homozygous individuals with formiminoglutamic aciduria (Majumdar 2017 PMID: 29178637, Ahrens-Nicklas 2019 PMID: 30740726). In 4 compound heterozygotes, the p.Leu536X variant was reported along with another disease-causing variant in FTCD, and these variants have been confirmed in trans in at least 1 individual. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 194395) and has been identified in 0.38% (286/75034) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0), which is consistent with a recessive carrier frequency and the clinical manifestations of the disease. This nonsense variant leads to a premature termination codon at position 536. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing the last 6 amino acids of the coding region. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive formiminoglutamic aciduria. ACMG/AMP Criteria applied: PM3_Strong, PVS1_Moderate.
OMIM RCV001199935 SCV001370720 pathogenic Glutamate formiminotransferase deficiency 2020-07-04 no assertion criteria provided literature only

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