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
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.
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.
Fulgent Genetics,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

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