ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.1498C>T (p.Pro500Ser)

gnomAD frequency: 0.00001  dbSNP: rs776371246
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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 RCV001879181 SCV002141868 uncertain significance Fanconi anemia 2022-05-30 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 500 of the FANCA protein (p.Pro500Ser). This variant is present in population databases (rs776371246, gnomAD 0.002%). 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: 1371829). 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 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002471173 SCV002767134 uncertain significance Fanconi anemia complementation group A 2019-08-28 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_000135.2(FANCA):c.1498C>T in exon 16 of 43 of the FANCA gene. This substitution is predicted to create a moderate amino acid change from a proline to a serine at position 500 of the protein, NP_000126.2(FANCA):p.(Pro500Ser). The proline at this position has moderate conservation (100 vertebrates, UCSC), and is located within the fanconi anaemia group A protein N-terminus domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0008% (2 heterozygotes, 0 homozygotes). This variant has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).

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