Submissions for variant NM_000135.4(FANCA):c.3971C>T (p.Pro1324Leu) (rs182657062)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494388	SCV000582809	likely pathogenic	not provided	2015-11-24	criteria provided, single submitter	clinical testing	The P1324L variant in the FANCA gene has previously been reported in a patient with Fanconi Anemia who also harbors a frameshift variant in the FANCA gene (Morgan et al., 1999). Functional studies showed that P1324L resulted in mild impairment of FANCA function (Adachi et al., 2002). The P1324L variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P1324L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The P1324L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Counsyl	RCV000666624	SCV000790945	likely pathogenic	Fanconi anemia, complementation group A	2017-04-17	criteria provided, single submitter	clinical testing
Invitae	RCV001219227	SCV001391153	pathogenic	Fanconi anemia	2020-06-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 1324 of the FANCA protein (p.Pro1324Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs182657062, ExAC 0.01%). This variant has been reported in many individuals affected with Fanconi anemia and is considered a common recurrent mutation (PMID: 10521298, 17924555, 23973728, 24584348). Experimental studies have shown that this missense change results in an altered sub-cellular localization pattern. Additional transfection experiments showed that this missense change partially disrupts FANCA protein phosphorylation its interactions with FANCC, FANCF and FANCD2 (PMID: 12444097). For these reasons, this variant has been classified as Pathogenic.
Leiden Open Variation Database	RCV000666624	SCV001426129	pathogenic	Fanconi anemia, complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.