ClinVar Miner

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

dbSNP: rs753063086
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Total submissions: 8
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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 likely pathogenic Fanconi anemia complementation group A 2021-09-22 criteria provided, single submitter clinical testing
Invitae RCV000809264 SCV000949410 pathogenic Fanconi anemia 2023-10-18 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). 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. 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 2023-07-31 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.
PreventionGenetics, part of Exact Sciences RCV003892520 SCV004714081 pathogenic FANCA-related condition 2024-02-19 criteria provided, single submitter 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.
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

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