Submissions for variant NM_000135.4(FANCA):c.3163C>T (p.Arg1055Trp)

dbSNP: rs753063086

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670742	SCV000795636	likely pathogenic	Fanconi anemia complementation group A	2017-11-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000670742	SCV000894101	pathogenic	Fanconi anemia complementation group A	2024-04-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809264	SCV000949410	pathogenic	Fanconi anemia	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1055 of the FANCA protein (p.Arg1055Trp). This variant is present in population databases (rs753063086, gnomAD 0.01%). This missense change has been observed in individuals with Fanconi anemia (PMID: 9929978, 10094191, 15523645, 19367192). ClinVar contains an entry for this variant (Variation ID: 555008). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FANCA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FANCA function (PMID: 12444097, 24349332, 28864460). This variant disrupts the p.Arg1055 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been observed in individuals with FANCA-related conditions (PMID: 24584348), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000670742	SCV004196065	pathogenic	Fanconi anemia complementation group A	2024-03-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478395	SCV004222001	pathogenic	not provided	2021-09-08	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because there are too few occurrences in population data. The variant was found in a symptomatic patient. 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. Another pathogenic or likely pathogenic variant affects the same amino acid. The variant occurs with multiple lone recessive pathogenic variants in the same gene. Functional studies have shown that this variant has a deleterious effect on protein function.
Leiden Open Variation Database	RCV000670742	SCV001425978	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV000670742	SCV001462888	pathogenic	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892520	SCV004714081	pathogenic	FANCA-related disorder	2024-02-19	no assertion criteria provided	clinical testing	The FANCA c.3163C>T variant is predicted to result in the amino acid substitution p.Arg1055Trp. This variant was reported to be causative for autosomal recessive Fanconi anemia, and functional studies support its pathogenicity (Nakamura et al. 1999. PubMed ID: 9929978; Yagasaki et al. 2004. PubMed ID: 15523645; Moghrabi et al. 2009. PubMed ID: 19367192; Qian et al. 2013. PubMed ID: 24349332; Wilkes et al. 2017. PubMed ID: 28864460). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/555008/). Different nucleotide substitutions affecting the same amino acid (p.Arg1055Gln, p.Arg1055Leu, p.Arg1055Gly) have also been reported in individuals with autosomal recessive Fanconi anemia (Human Gene Mutation Database). Taken together, the c.3163C>T (p.Arg1055Trp) variant is interpreted as pathogenic.
Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	RCV000670742	SCV004800928	likely pathogenic	Fanconi anemia complementation group A		no assertion criteria provided	research