ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.440C>T (p.Pro147Leu) (rs730881711)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160470 SCV000211035 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing This variant is denoted FANCC c.440C>T at the cDNA level, p.Pro147Leu (P147L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Pro147Leu was not observed at a significant frequency in large population cohorts (Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. FANCC Pro147Leu occurs at a position that is conserved in mammals and is located in the binding regions for GRP94, FAZF, RED, and Hsp70 (Gordon and Buchwald 2000). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether FANCC Pro147Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000205386 SCV000260776 uncertain significance Fanconi anemia 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 147 of the FANCC protein (p.Pro147Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs730881711, ExAC 0.003%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 182469). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001167422 SCV001329921 uncertain significance Fanconi anemia, complementation group C 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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