Submissions for variant NM_001365951.3(KIF1B):c.2042G>A (p.Arg681Lys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003485841	SCV003814561	uncertain significance	Charcot-Marie-Tooth disease type 2A1	2021-10-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004246010	SCV004097306	uncertain significance	not specified	2023-06-30	criteria provided, single submitter	clinical testing	The p.R635K variant (also known as c.1904G>A), located in coding exon 18 of the KIF1B gene, results from a G to A substitution at nucleotide position 1904. The amino acid change results in arginine to lysine at codon 635, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 18, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005060954	SCV005723044	uncertain significance	Charcot-Marie-Tooth disease type 2	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 635 of the KIF1B protein (p.Arg635Lys). This variant also falls at the last nucleotide of exon 19, which is part of the consensus splice site for this exon. This variant is present in population databases (rs751423624, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with KIF1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 2433134). 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 disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.