ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1327A>G (p.Met443Val) (rs150941781)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219780 SCV000279310 uncertain significance not provided 2015-11-16 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1327A>G at the cDNA level, p.Met443Val (M443V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. FANCC Met443Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. FANCC Met443Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is not located in a known functional domain (UniProt). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may destroy the natural splice donor site for intron 13 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether FANCC Met443Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000821830 SCV000962602 uncertain significance Fanconi anemia 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 443 of the FANCC protein (p.Met443Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs150941781, 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: 234476). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.

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