Submissions for variant NM_000135.4(FANCA):c.2444C>T (p.Pro815Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002942004	SCV003267494	uncertain significance	Fanconi anemia	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 815 of the FANCA protein (p.Pro815Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs778009295, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003409969	SCV004107399	uncertain significance	FANCA-related disorder	2023-03-07	criteria provided, single submitter	clinical testing	The FANCA c.2444C>T variant is predicted to result in the amino acid substitution p.Pro815Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89836305-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.