ClinVar Miner

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

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Total submissions: 4
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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.

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