ClinVar Miner

Submissions for variant NM_206965.2(FTCD):c.990dup (p.Pro331fs) (rs398124234)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000081452 SCV000233112 pathogenic not provided 2016-06-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV000004234 SCV000245484 pathogenic GLUTAMATE FORMIMINOTRANSFERASE DEFICIENCY 2014-10-18 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant [T453M] in a 54-year-old male with episodic neurological decompensation (weakness, ataxia, altered mental status with protein meals), learning disability, osteopenia, non-cancerous adrenal adenomas, and a diagnosis of multiple sclerosis and toxic encephalopathy due to exposure to organic solvents. Variant pathogenic in recessive state; heterozygotes are carriers.
GeneDx RCV000081452 SCV000568833 likely pathogenic not provided 2016-04-06 criteria provided, single submitter clinical testing The c.990dupG variant in the FTCD gene has been reported previously in association with glutamate formiminotransferase deficiency, when present in the homozygous state or when in trans with another variant. (Scolamiero et al., 2015; Hilton et al., 2003). Functional studies show the c.990dupG variant results in a truncated protein and loss of the cyclodeaminase domain, and even though formiminotransferase activies remained intact the authors suggest the second reaction is unable to be complete (Hilton et al., 2003). The c.990dupG variant causes a frameshift starting with codon Proline 331, changes this amino acid to a Alanine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Pro331AlafsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Population data reported for this variant by the NHLBI Exome Sequencing Project are unreliable due to the number of reported homozygous individuals (7/4773) exceeding that which would be expected according to Hardy-Weinberg equilibrium. The c.990dupG variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
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 2020-08-25 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to be homozygous or in combination with another FTCD variant in several individuals affected with glutamate formiminotransferase deficiency and has been observed to segregate with disease in one family (PMID: 12815595, 29869163, 29178637). This variant is also known as c.1033insG in the literature. 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.
OMIM RCV000004234 SCV000024400 pathogenic GLUTAMATE FORMIMINOTRANSFERASE DEFICIENCY 2003-07-01 no assertion criteria provided literature only

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