ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1642C>T (p.Arg548Ter) (rs104886457)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058924 SCV000211058 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted FANCC c.1642C>T at the cDNA level and p.Arg548Ter (R548X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through protein truncation. This variant has been reported in several individuals with Fanconi anemia, in both the homozygous and compound heterozygous state, and is known to cause premature termination of translation (Murer-Orlando 1993, Gibson 1996, Gillio 1997, De Rocco 2014, Wenger 2016). A functional study showed that FANCC Arg548Ter was unable to correct the cellular Fanconi Anemia phenotype in transfected cells and that the presence of the C-terminal region is functionally necessary (Lo ten Foe 1996). We therefore consider this variant to be pathogenic.
Invitae RCV000205197 SCV000261073 pathogenic Fanconi anemia 2018-12-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the FANCC mRNA at codon 548 (p.Arg548*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated FANCC protein lacking the last 11 amino acid residues. This variant is present in population databases (rs104886457, ExAC 0.005%). This variant has been reported as homozygous and in trans with a second loss-of-function variant in individuals affected with Fanconi anemia (PMID: 8103176, 24584348). ClinVar contains an entry for this variant (Variation ID: 12047). An experimental study has shown that this nonsense change renders FANCC unable to correct the hypersensitivity to mitomycin C in a Fanconi anemia cell line (PMID: 8882868), suggesting that the very C-terminal amino acids are critical for proper FANCC function. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515355 SCV000611188 pathogenic Fanconi anemia, complementation group C; Tracheoesophageal fistula 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572840 SCV000673286 pathogenic Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Counsyl RCV000012827 SCV000677975 likely pathogenic Fanconi anemia, complementation group C 2015-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000012827 SCV000695427 pathogenic Fanconi anemia, complementation group C 2016-08-31 criteria provided, single submitter clinical testing Variant summary: The c.1642C>T (p.Arg548*) variant in FANCC gene is a nonsense change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The p.Arg548* is expected to lack last 11 amino acids and was unable to restore MMC hypersensitivity in the functional assay. The variant is present in the large control population dataset of ExAC at a low frequency 0.00002 (3/120522 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.002) in this gene. The variant of interest has been reported in multiple affected individuals in homozygous or compound heterozygous state with a confirmed diagnosis of FA. Per multiple reports, this variant is strongly correlated with increased numbers of severe congenital malformation, earlier onsets of marrow failure, and overall poorer survival rate. In addition, multiple reputable databases/clinical laboratories classified this variant as Pathogenic. Taken together, the variant was classified as Pathogenic.
Mendelics RCV000012827 SCV000838339 pathogenic Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012827 SCV000894483 pathogenic Fanconi anemia, complementation group C 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000205197 SCV000967666 pathogenic Fanconi anemia 2018-05-14 criteria provided, single submitter clinical testing The p.Arg548X variant in FANCC has been identified in the homozygous or compound heterozygous state in more than 9 individuals with Fanconi anemia, and segregat ed with disease in at least 1 affected family member (Murer-Orlando 1993, Gillio 1997, Aftab 2017). This variant has also been identified in 8/111606 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs104886457). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrie r frequency. This nonsense variant leads to a premature termination codon at pos ition 548. This alteration occurs within the last exon and is more likely to esc ape nonsense mediated decay (NMD) and result in a truncated protein. Nevertheles s, in vitro functional studies provide evidence that this variant disrupts FANCC function (Lo Ten Foe 1996). In summary, this variant meets criteria to be class ified as pathogenic for autosomal recessive Fanconi anemia. ACMG/AMP Criteria ap plied: PM3_Very Strong; PM4; PS3_Moderate.
OMIM RCV000012827 SCV000033067 pathogenic Fanconi anemia, complementation group C 1993-09-11 no assertion criteria provided literature only
GeneReviews RCV000012827 SCV000057805 pathogenic Fanconi anemia, complementation group C 2016-09-22 no assertion criteria provided literature only
SNPedia RCV000058924 SCV000090445 not provided not provided no assertion provided not provided

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