ClinVar Miner

Submissions for variant NM_033084.5(FANCD2):c.1954G>A (p.Val652Ile) (rs1381447946)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000533607 SCV000626468 uncertain significance Fanconi anemia 2017-03-29 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 652 of the FANCD2 protein (p.Val652Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Fanconi anemia who also carried a homozygous FANCD2 splice variant, and showed hematopoietic mosaicism (PMID: 17436244). However, it is unclear if it was a germline or somatic variant. 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 isoleucine 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in an affected individual in the mosaic state, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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