ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.520C>T (p.Arg174Ter) (rs781542763)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169411 SCV000220815 likely pathogenic Fanconi anemia, complementation group C 2014-10-17 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169411 SCV000919322 pathogenic Fanconi anemia, complementation group C 2018-09-20 criteria provided, single submitter clinical testing Variant summary: FANCC c.520C>T (p.Arg174X) 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. 5/5 computational tools predict no significant impact on normal splicing, however one publication reports the variant to result in skipping of exon 6 (LoTen Foe_1998). The variant allele was found at a frequency of 1.6e-05 in 245902 control chromosomes (gnomAD). The variant, c.520C>T, has been reported in the literature in one individual affected with Fanconi Anemia Group C (LoTen Foe_1998). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001213440 SCV001385070 pathogenic Fanconi anemia 2019-07-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg174*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs781542763, ExAC 0.01%). This variant co-occurs with a pathogenic variant (c.456+4A>T) in FANCC in an individual affected with Fanconi anemia (PMID: 9452030). ClinVar contains an entry for this variant (Variation ID: 189022). This variant is also known as c.775C>T in the literature. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
Leiden Open Variation Database RCV000169411 SCV001365299 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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