ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.37C>T (p.Gln13Ter) (rs121917784)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115351 SCV000149260 pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted FANCC c.37C>T at the cDNA level and p.Gln13Ter (Q13X) at the protein level. The substitution creates a nonsense variant, changing a Glutamine to a premature stop codon (CAG>TAG). This variant has been reported in the homozygous and compound heterozygous state in individuals with Fanconi Anemia (Murer-Orlando 1993, Verlander 1994, Gillio 1997, Nicchia 2015) and it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Thus, we consider this variant to be pathogenic.
Counsyl RCV000012826 SCV000220353 likely pathogenic Fanconi anemia, complementation group C 2014-05-27 criteria provided, single submitter literature only
Invitae RCV000476519 SCV000549951 pathogenic Fanconi anemia 2020-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln13*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121917784, ExAC 0.002%). This variant has been observed as homozygous or with other FANCC pathogenic variants in individuals affected with Fanconi anemia (PMID: 8103176, 9207444, 8128956, 26740942). This variant is also known as c.292C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 12046). Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012826 SCV000917333 pathogenic Fanconi anemia, complementation group C 2018-02-15 criteria provided, single submitter clinical testing Variant summary: FANCC c.37C>T (p.Gln13X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.65G>A, p.Trp22X; c.553C>T, p.Arg185X; c.1642C>T, p.Arg548X). The variant allele was found at a frequency of 8.1e-06 in 245648 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (8.1e-06 vs 1.80E-03), allowing no conclusion about variant significance. c.37C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia Group C (De Rocco_2014, Gillio_1997, Susswein_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000012826 SCV001163262 pathogenic Fanconi anemia, complementation group C criteria provided, single submitter clinical testing
Ambry Genetics RCV001021181 SCV001182762 pathogenic Hereditary cancer-predisposing syndrome 2018-04-21 criteria provided, single submitter clinical testing The p.Q13* pathogenic mutation (also known as c.37C>T), located in coding exon 1 of the FANCC gene, results from a C to T substitution at nucleotide position 37. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration has been reported in the homozygous and compound heterozygous state in multiple individuals with a clinical diagnosis of Fanconi anemia (Verlander PC et al. Am. J. Hum. Genet., 1994 Apr;54:595-601; Murer-Orlando M et al. Lancet, 1993 Sep;342:686; Gillio AP et al. Blood, 1997 Jul;90:105-10; Nicchia E et al. Mol Genet Genomic Med, 2015 Nov;3:500-12). In addition to the information presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
OMIM RCV000012826 SCV000033066 pathogenic Fanconi anemia, complementation group C 1993-09-11 no assertion criteria provided literature only
GeneReviews RCV000012826 SCV000057807 pathogenic Fanconi anemia, complementation group C 2021-06-01 no assertion criteria provided literature only Common in northern Europeans
Leiden Open Variation Database RCV000012826 SCV001365306 pathogenic Fanconi anemia, complementation group C 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

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