ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1162G>A (p.Gly388Arg) (rs371897078)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205129 SCV000260584 uncertain significance Fanconi anemia 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 388 of the FANCC protein (p.Gly388Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs371897078, ExAC 0.01%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 220210). 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 arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000484234 SCV000564979 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1162G>A at the cDNA level, p.Gly388Arg (G388R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Gly388Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Gly388Arg occurs at a position that is not conserved and is located within the Hsp70 binding domain (Gordon 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 Gly388Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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