Submissions for variant NM_000135.4(FANCA):c.971T>G (p.Leu324Arg)

gnomAD frequency: 0.00001  dbSNP: rs1447363475

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527193	SCV000626227	pathogenic	Fanconi anemia	2024-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 324 of the FANCA protein (p.Leu324Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 12697994; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 456147). 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 expected to disrupt FANCA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FANCA function (PMID: 12697994). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000673548	SCV000798761	uncertain significance	Fanconi anemia complementation group A	2018-03-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000673548	SCV002024573	likely pathogenic	Fanconi anemia complementation group A	2019-01-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005001074	SCV005625532	likely pathogenic	not provided	2024-03-29	criteria provided, single submitter	clinical testing	The FANCA c.971T>G (p.Leu324Arg) variant has been reported in the published literature occurring with a second pathogenic FANCA variant in an individual with Fanconi Anemia (PMID: 12697994 (2002)). Additionally, experimental studies suggest this variant is damaging to protein function (PMID: 12697994 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, this variant is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000673548	SCV005646677	likely pathogenic	Fanconi anemia complementation group A	2024-01-10	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000673548	SCV001426040	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.