ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.65G>A (p.Trp22Ter)

gnomAD frequency: 0.00002  dbSNP: rs377294947
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169293 SCV000220611 likely pathogenic Fanconi anemia complementation group C 2014-08-20 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169293 SCV000695435 pathogenic Fanconi anemia complementation group C 2017-08-14 criteria provided, single submitter clinical testing Variant summary: The FANCC c.65G>A (p.Trp22X) variant results in a premature termination codon, predicted to cause a truncated or absent FANCC 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 (e.g.c.67delG/p.Asp23fsX23, c.1642C>T/p.Arg548X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121148 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). This variant has been reported in at least three patients with Fanconi Anemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000169293 SCV000894485 pathogenic Fanconi anemia complementation group C 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000169293 SCV001163260 pathogenic Fanconi anemia complementation group C 2023-12-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001390247 SCV001591920 pathogenic Fanconi anemia 2023-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp22*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs377294947, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 8844212, 28717661). ClinVar contains an entry for this variant (Variation ID: 188926). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002362865 SCV002663424 pathogenic Hereditary cancer-predisposing syndrome 2024-08-14 criteria provided, single submitter clinical testing The p.W22* pathogenic mutation (also known as c.65G>A), located in coding exon 1 of the FANCC gene, results from a G to A substitution at nucleotide position 65. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration has been identified in the homozygous state in several patients with Fanconi Anemia (Gibson RA et al. Hum Mutat. 1996;8:140-8; Ameziane N et al. Hum Mutat. 2008 Jan;29:159-66; Pilonetto DV et al. Mol Genet Genomic Med. 2017 Jul;5:360-372). In addition to the clinical data 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.
PreventionGenetics, part of Exact Sciences RCV003407628 SCV004106264 pathogenic FANCC-related disorder 2023-04-10 criteria provided, single submitter clinical testing The FANCC c.65G>A variant is predicted to result in premature protein termination (p.Trp22*). This variant has been reported in the homozygous state in at least two patients with Fanconi anaemia (Gibson et al. 1996. PubMed ID: 8844212; Ameziane et al. 2008. PubMed ID: 17924555). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-98011509-C-T). Nonsense variants in FANCC are expected to be pathogenic. This variant is interpreted as pathogenic.
GeneDx RCV004719732 SCV005325764 pathogenic not provided 2023-09-25 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34774576, 29922827, 17924555, 12670332, 28717661, 8844212, 27832981, Rodriguez2005[article])
Leiden Open Variation Database RCV000169293 SCV001365307 pathogenic Fanconi anemia complementation group C 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter.
Natera, Inc. RCV001390247 SCV002081314 pathogenic Fanconi anemia 2017-03-17 no assertion criteria provided clinical testing

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