Submissions for variant NM_000135.4(FANCA):c.1304G>T (p.Arg435Leu)

dbSNP: rs1060501879

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672654	SCV000797780	uncertain significance	Fanconi anemia complementation group A	2018-02-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378203	SCV001575724	pathogenic	Fanconi anemia	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 435 of the FANCA protein (p.Arg435Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FANCA-related conditions (PMID: 23613520). 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: 556625). 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: 29098742). This variant disrupts the p.Arg435 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10090479, 11739169, 12444097, 15523645, 19367192, 29098742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000672654	SCV004196616	likely pathogenic	Fanconi anemia complementation group A	2022-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001378203	SCV005203338	likely pathogenic	Fanconi anemia	2024-07-05	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.1304G>T (p.Arg435Leu) results in a non-conservative amino acid change located in the anconi anaemia group A protein, N-terminal domain (IPR031729) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250930 control chromosomes. c.1304G>T has been reported in the literature as compound heterozygous genotype in two individuals affected with Fanconi Anemia (Chandrasekharappa_2013, Kimble_2018). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1303C>T, p.Arg435Cys), supporting the critical relevance of codon 435 to FANCA protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23613520, 29098742). ClinVar contains an entry for this variant (Variation ID: 556625). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Leiden Open Variation Database	RCV000672654	SCV001425784	uncertain significance	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.