Submissions for variant NM_000136.3(FANCC):c.371C>T (p.Ala124Val)

dbSNP: rs374602991

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160472	SCV000211037	uncertain significance	not provided	2014-04-05	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.371C>T at the cDNA level, p.Ala124Val (A124V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Ala124Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution and is unlikely to affect protein integrity. FANCC Ala124Val occurs at a position that is well conserved across species and is located in the RED domain (Gordon 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether FANCC Ala124Val is pathogenic or benign. We consider it to be a variant of uncertain significance. Furthermore, FANCC has been only recently described in association with cancer predisposition and the risks are not well understood.
Invitae	RCV000799139	SCV000938790	uncertain significance	Fanconi anemia	2023-04-26	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 182471). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. This variant is present in population databases (rs374602991, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 124 of the FANCC protein (p.Ala124Val).
Ambry Genetics	RCV002345551	SCV002621395	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-25	criteria provided, single submitter	clinical testing	The p.A124V variant (also known as c.371C>T), located in coding exon 4 of the FANCC gene, results from a C to T substitution at nucleotide position 371. The alanine at codon 124 is replaced by valine, an amino acid with 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.	RCV001276594	SCV001463021	uncertain significance	Fanconi anemia complementation group C	2020-01-17	no assertion criteria provided	clinical testing