Submissions for variant NM_022725.4(FANCF):c.573C>G (p.Ser191Arg)

gnomAD frequency: 0.00024  dbSNP: rs146219377

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557500	SCV000626390	uncertain significance	Fanconi anemia	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 191 of the FANCF protein (p.Ser191Arg). This variant is present in population databases (rs146219377, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with FANCF-related conditions. ClinVar contains an entry for this variant (Variation ID: 456284). 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 not expected to disrupt FANCF 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.
Fulgent Genetics, Fulgent Genetics	RCV000764967	SCV000896144	uncertain significance	Fanconi anemia complementation group F	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001545711	SCV001765092	likely benign	not provided	2020-12-31	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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001545711	SCV002011029	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821485	SCV002068953	uncertain significance	not specified	2019-12-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCF gene demonstrated a sequence change, c.573C>G, in exon 1 that results in an amino acid change, p.Ser191Arg. This sequence change does not appear to have been previously described in patients with FANCF-related disorders and has been described in the gnomAD database with a frequency of 0.085% in African populations (dbSNP rs146219377). The p.Ser191Arg change affects a poorly conserved amino acid residue located in a domain of the FANCF protein that is not known to be functional. The p.Ser191Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Ambry Genetics	RCV002527669	SCV003574591	likely benign	Inborn genetic diseases	2021-08-10	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.