Submissions for variant NM_000135.4(FANCA):c.4198C>T (p.Arg1400Cys)

gnomAD frequency: 0.00001  dbSNP: rs745882980

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670597	SCV000795469	likely pathogenic	Fanconi anemia complementation group A	2017-11-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000670597	SCV000894099	likely pathogenic	Fanconi anemia complementation group A	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000801328	SCV000941102	pathogenic	Fanconi anemia	2023-01-09	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg1400 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been observed in individuals with FANCA-related conditions (PMID: 17924555, 29098742, 30792206), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 554887). This missense change has been observed in individuals with Fanconi anemia (PMID: 15643609, 21273304, 24584348, 28102861, 28717661, 29098742). This variant is present in population databases (rs745882980, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1400 of the FANCA protein (p.Arg1400Cys). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000801328	SCV001983401	pathogenic	Fanconi anemia	2021-09-28	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.4198C>T (p.Arg1400Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251486 control chromosomes. c.4198C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia (example, Levran_2005, Castella_2011, De Rocco_2014, Muramatsu_2017, Pilonetto_2017, Kimble_2018, Mori_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one database (LOVD) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000670597	SCV002024569	likely pathogenic	Fanconi anemia complementation group A	2019-05-06	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000670597	SCV004176509	pathogenic	Fanconi anemia complementation group A	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.4198C>T(p.Arg1400Cys) variant in FANCA gene has been reported previously in multiple individuals affected with Fanconi anemia (Kimble DC, et. al., 2018; Pilonetto DV, et. al., 2017). The p.Arg1400Cys variant has been reported with allele frequency of 0.001% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg1400Cys in FANCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 1400 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in FANCA gene, the molecular diagnosis is not confirmed.
Baylor Genetics	RCV000670597	SCV004196107	pathogenic	Fanconi anemia complementation group A	2023-05-25	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000670597	SCV001425870	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto.
Natera, Inc.	RCV000801328	SCV002092470	pathogenic	Fanconi anemia	2021-05-27	no assertion criteria provided	clinical testing