ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.974C>T (p.Ala325Val)

gnomAD frequency: 0.00006  dbSNP: rs367618818
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115365 SCV000149274 uncertain significance not provided 2022-11-29 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Gordon2000[Book])
Invitae RCV000630831 SCV000751799 uncertain significance Fanconi anemia 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 325 of the FANCC protein (p.Ala325Val). This variant is present in population databases (rs367618818, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 127551). 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: "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.
Ambry Genetics RCV001019698 SCV001181089 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-24 criteria provided, single submitter clinical testing The p.A325V variant (also known as c.974C>T), located in coding exon 9 of the FANCC gene, results from a C to T substitution at nucleotide position 974. The alanine at codon 325 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago RCV001818269 SCV002070128 uncertain significance not specified 2020-02-14 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.974C>T, in exon 10 that results in an amino acid change, p.Ala325Val. This sequence change does not appear to have been previously described in patients with FANCC-related disorders and has been described in the gnomAD database with a frequency of 0.03% in the African sub-population (dbSNP rs367618818). The p.Ala325Val change affects a moderately conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala325Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala325Val change remains unknown at this time.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115365 SCV002774570 uncertain significance not provided 2023-03-17 criteria provided, single submitter clinical testing The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00028 (7/24970 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics RCV002483186 SCV002793986 uncertain significance Fanconi anemia complementation group C 2022-05-27 criteria provided, single submitter clinical testing
Natera, Inc. RCV000630831 SCV002081197 uncertain significance Fanconi anemia 2018-08-09 no assertion criteria provided clinical testing

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