ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3391A>G (p.Thr1131Ala) (rs574034197)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665186 SCV000789260 likely pathogenic Fanconi anemia, complementation group A 2017-01-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000665186 SCV000894100 likely pathogenic Fanconi anemia, complementation group A 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000498721 SCV000589393 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing The T1131A variant in the FANCA gene has been reported previously in the homozygous state and with large intragenic deletions in individuals with Fanconi anemia-complementation group A (Gille et al., 2012; Levran et al., 2005; Moghrabi et al., 2009; Ameziane et al., 2008). The T1131A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1131A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies show that the T1131A variant significantly decreases FANCD2 monoubiquitination and the number of FANCD2 foci before and after mitomyocin C treatment (Wilkes et al., 2017). We interpret T1131A as a pathogenic variant.
Invitae RCV000230300 SCV000283560 pathogenic Fanconi anemia 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1131 of the FANCA protein (p.Thr1131Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs574034197, ExAC 0.02%). This variant has been reported in several families with Fanconi anemia (PMID: 9371798, 12444097, 22778927, 19367192, 1792455, 15643609, 19278965). In one affected individual this variant was homozygous and in three individuals it co-occurred with a different subgenic FANCA deletions on the opposite chromosome. ClinVar contains an entry for this variant (Variation ID: 237048). This missense substitution behaves normally in multiple in vitro experiments and a cell survival assay (PMID: 12444097). However, in vivo mRNA and protein expression analyses have not been performed and this variant has not been tested in a complementation assay. At this time, the functional impact of this missense change is indeterminate. In summary, this is a rare missense variant that has been reported in several individuals with Fanconi anemia. Although functional experiments failed to demonstrate a deleterious effect associated with this variant, the clinical evidence is sufficient to classify this variant as Pathogenic.

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