Submissions for variant NM_000136.3(FANCC):c.1144C>G (p.Gln382Glu)

gnomAD frequency: 0.00002  dbSNP: rs778968824

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218892	SCV000279848	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.1144C>G at the cDNA level, p.Gln382Glu (Q382E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Gln382Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. FANCC Gln382Glu occurs at a position that is not conserved and is located within a region of interaction with Hsp70 (Gordon & Buchwald 2000). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether FANCC Gln382Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001828093	SCV002254327	uncertain significance	Fanconi anemia	2022-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 382 of the FANCC protein (p.Gln382Glu). This variant is present in population databases (rs778968824, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 234807). 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 FANCC 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.
Ambry Genetics	RCV002450653	SCV002614728	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing	The p.Q382E variant (also known as c.1144C>G), located in coding exon 11 of the FANCC gene, results from a C to G substitution at nucleotide position 1144. The glutamine at codon 382 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001828093	SCV002081176	uncertain significance	Fanconi anemia	2018-09-03	no assertion criteria provided	clinical testing