ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.1470G>C (p.Gln490His)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001068184 SCV001233278 uncertain significance Fanconi anemia 2019-03-05 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 490 of the FANCA protein (p.Gln490His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 15 of the FANCA coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Fanconi anemia (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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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