Submissions for variant NM_000135.4(FANCA):c.4285G>A (p.Asp1429Asn)

dbSNP: rs748856769

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001115282	SCV001273248	uncertain significance	Fanconi anemia complementation group A	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001207580	SCV001378942	likely pathogenic	Fanconi anemia	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1429 of the FANCA protein (p.Asp1429Asn). This variant is present in population databases (rs748856769, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Fanconi anemia (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: 884284). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002480486	SCV002774553	uncertain significance	not provided	2021-06-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001207580	SCV002092462	uncertain significance	Fanconi anemia	2020-01-21	no assertion criteria provided	clinical testing