ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1264C>A (p.Leu422Met) (rs756716463)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478222 SCV000564980 uncertain significance not provided 2016-11-08 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1264C>A at the cDNA level, p.Leu422Met (L422M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Leu422Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. FANCC Leu422Met occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the Hsp70 biding domain (Gordon 2000). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FANCC Leu422Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000702767 SCV000831635 uncertain significance Fanconi anemia 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 422 of the FANCC protein (p.Leu422Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs756716463, ExAC 0.07%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 418189). 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: "Deleterious"; PolyPhen-2: "Possibly 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.

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