Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000230300 | SCV000283560 | pathogenic | Fanconi anemia | 2019-10-17 | 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. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
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. |
| Fulgent Genetics, |
RCV000665186 | SCV000894100 | likely pathogenic | Fanconi anemia, complementation group A | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000665186 | SCV000789260 | likely pathogenic | Fanconi anemia, complementation group A | 2017-01-17 | no assertion criteria provided | clinical testing | |
| Leiden Open Variation Database | RCV000665186 | SCV001425707 | pathogenic | Fanconi anemia, complementation group A | 2020-02-28 | no assertion criteria provided | curation | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, Sue Richards. |