ClinVar Miner

Submissions for variant NM_006267.5(RANBP2):c.4972T>G (p.Phe1658Val)

gnomAD frequency: 0.00001  dbSNP: rs755016899
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489412 SCV000576930 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing The F1658V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F1658V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F1658V variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000646004 SCV000767759 uncertain significance Familial acute necrotizing encephalopathy 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 1658 of the RANBP2 protein (p.Phe1658Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is present in population databases (rs755016899, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with RANBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 426479). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). 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 RCV004023250 SCV004934407 uncertain significance not specified 2023-12-11 criteria provided, single submitter clinical testing The c.4972T>G (p.F1658V) alteration is located in exon 20 (coding exon 20) of the RANBP2 gene. This alteration results from a T to G substitution at nucleotide position 4972, causing the phenylalanine (F) at amino acid position 1658 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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