ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1244C>T (p.Ala415Val) (rs550462055)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485470 SCV000566219 uncertain significance not provided 2016-06-15 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1244C>T at the cDNA level, p.Ala415Val (A415V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Ala415Val was not observed at significant allele frequency in 1000 Genomes (McVean 2012). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. FANCC Ala415Val occurs at a position that is not conserved across species and is located within the Hsp70 interaction region (Gordon 2000). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether FANCC Ala415Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570574 SCV000673343 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000630858 SCV000751829 uncertain significance Fanconi anemia 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 415 of the FANCC protein (p.Ala415Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 418852). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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