Submissions for variant NM_021922.3(FANCE):c.206G>A (p.Arg69Gln)

gnomAD frequency: 0.00026  dbSNP: rs758238449

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537323	SCV000650814	uncertain significance	Fanconi anemia complementation group E	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 69 of the FANCE protein (p.Arg69Gln). This variant is present in population databases (rs758238449, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with FANCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 471924). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000537323	SCV001317431	uncertain significance	Fanconi anemia complementation group E	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000537323	SCV001481585	uncertain significance	Fanconi anemia complementation group E	2019-12-07	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001797103	SCV002038830	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001821581	SCV002065622	uncertain significance	not specified	2021-08-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCE gene demonstrated a sequence change, c.206G>A, in exon 1 that results in an amino acid change, p.Arg69Gln. This sequence change has been described in the gnomAD database with frequency of 0.089% in the African American/African subpopulation (dbSNP rs758238449). The p.Arg69Gln change affects a poorly conserved amino acid residue located in a domain of the FANCE protein that is not known to be functional. The p.Arg69Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with FANCE-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg69Gln change remains unknown at this time.
Ambry Genetics	RCV002530181	SCV003682152	likely benign	Inborn genetic diseases	2021-12-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.