Submissions for variant NM_000136.3(FANCC):c.748C>A (p.Leu250Ile) (rs778966663)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221352	SCV000279322	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.748C>A at the cDNA level, p.Leu250Ile (L250I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Leu250Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. FANCC Leu250Ile occurs at a position that is conserved across species and is located in a region responsible for interaction with GRP94 and Hsp70 (Gordon 2000). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FANCC Leu250Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000630840	SCV000751809	uncertain significance	Fanconi anemia	2017-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with isoleucine at codon 250 of the FANCC protein (p.Leu250Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs778966663, ExAC 0.002%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 234480). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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