ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1069C>T (p.Gln357Ter) (rs759900071)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483955 SCV000566937 pathogenic not provided 2019-04-12 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26740942)
Invitae RCV001035863 SCV001199202 pathogenic Fanconi anemia 2020-09-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln357*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs759900071, ExAC 0.002%). This variant has been observed in an affected with Fanconi anemia (PMID: 26740942). ClinVar contains an entry for this variant (Variation ID: 419252). Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000984263 SCV001132389 likely pathogenic Fanconi anemia, complementation group C 2014-01-02 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000483955 SCV001551748 likely pathogenic not provided no assertion criteria provided clinical testing The FANCC p.Gln357X variant was identified in 1 of 56 proband chromosomes (frequency: 0.02) from individuals or families of Italian ethnicity with Fanconi anemia (Nicchia 2015); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in dbSNP (ID: rs759900071) as “With Pathogenic allele”, and in the ClinVar and Clinvitae databases as pathogenic by GeneDx. The variant was not identified in Cosmic, MutDB and LOVD 3.0 databases or in the 1000 Genomes and NHLBI GO Exome Sequencing projects. The variant was identified in control databases in 1 of 246096 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 111662 chromosomes (freq: 0.00001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The c.1069C>T variant leads to a premature stop codon at position 357, which is predicted to lead to a truncated or absent protein, and loss of function. Loss of function variants of the FANCC gene are an established mechanism of disease in Fanconi anemia and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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