ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.844-1G>C (rs774209201)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169449 SCV000220870 likely pathogenic Fanconi anemia, complementation group C 2014-11-12 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224795 SCV000281409 pathogenic not provided 2015-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000224795 SCV000517421 pathogenic not provided 2018-01-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted FANCC c.844-1G>C or IVS8-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 8 of the FANCC gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in the compound heterozygous state with other truncating FANCC variants in at least two individuals with Fanconi Anemia (Ameziane 2008). We consider FANCC c.844-1G>C to be pathogenic.
Invitae RCV000462508 SCV000549969 likely pathogenic Fanconi anemia 2018-10-03 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the FANCC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs774209201, ExAC 0.002%). This variant has been observed in compound heterozygosity with two different pathogenic FANCC variants in two patients with suspected Fanconi anemia (PMID: 17924555). ClinVar contains an entry for this variant (Variation ID: 189053). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). 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.
Integrated Genetics/Laboratory Corporation of America RCV000169449 SCV000917334 likely pathogenic Fanconi anemia, complementation group C 2017-12-18 criteria provided, single submitter clinical testing Variant summary: The FANCC c.844-1G>C variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict the variant to abolish a cannonical splice acceptor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/246200 control chromosomes (gnomAD) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). The variant has been reported, to our knowledge, in one publication citing two affected individuals (Ameziane_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as likely pathogenic.

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