ClinVar Miner

Submissions for variant NM_001365951.3(KIF1B):c.3892A>G (p.Ile1298Val)

dbSNP: rs529804940
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000804284 SCV000944187 uncertain significance Charcot-Marie-Tooth disease type 2 2023-07-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1252 of the KIF1B protein (p.Ile1252Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 649366). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Molecular Genetics Laboratory, London Health Sciences Centre RCV001174210 SCV001337336 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Ambry Genetics RCV004028166 SCV005026673 uncertain significance not specified 2023-12-12 criteria provided, single submitter clinical testing The p.I1252V variant (also known as c.3754A>G), located in coding exon 34 of the KIF1B gene, results from an A to G substitution at nucleotide position 3754. The isoleucine at codon 1252 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Neuberg Centre For Genomic Medicine, NCGM RCV004818038 SCV005438705 uncertain significance Charcot-Marie-Tooth disease type 2A1 2023-07-22 criteria provided, single submitter clinical testing The observed missense variant c.3892A>Gp.Ile1298Val in KIF1B gene has been reported previously in individuals with Charcot-Marie-Tooth disease Volodarsky M, et al., 2021. The p.Ile1298Val variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. Computational evidence Polyphen-Benign, SIFT-Tolerated and Mutation Taster-Disease causing predicts conflicting evidence on protein structure and function for this variant.The amino acid Ile at position 1298 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Ile1298Val in KIF1B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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