ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.668C>T (p.Ala223Val)

dbSNP: rs749362808
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001372911 SCV001569606 uncertain significance Fanconi anemia 2021-08-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 223 of the FANCA protein (p.Ala223Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs749362808, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. 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. 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.
Genetic Services Laboratory, University of Chicago RCV001820076 SCV002070135 uncertain significance not specified 2020-02-05 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.668C>T, in exon 7 that results in an amino acid change, p.Ala223Val. This sequence change does not appear to have been previously described in patients with FANCA-related disorders and has been described in the gnomAD database in one individual (dbSNP rs749362808). The p.Ala223Val 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.Ala223Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Ala223Val change remains unknown at this time.

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