ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.2308C>T (p.Arg770Cys)

gnomAD frequency: 0.00003  dbSNP: rs1354855145
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001822663 SCV002071848 uncertain significance not specified 2021-08-30 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.2308C>T, in exon 25 that results in an amino acid change, p.Arg770Cys. This sequence change has been described in the gnomAD database with a frequency of 0.0057% in the East Asian subpopulation (dbSNP rs1354855145). The p.Arg770Cys change affects a poorly conserved amino acid residue located in a domain of the FANCA protein that is not known to be functional. The p.Arg770Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with FANCA-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg770Cys change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV001885353 SCV002288203 uncertain significance Fanconi anemia 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 770 of the FANCA protein (p.Arg770Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1338065). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCA protein function with a negative predictive value of 80%. 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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