Submissions for variant NM_001365951.3(KIF1B):c.2611G>A (p.Glu871Lys)

gnomAD frequency: 0.00004  dbSNP: rs763122049

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414814	SCV000492549	uncertain significance	Joint laxity; EMG abnormality; EMG: myopathic abnormalities; Pain	2015-09-23	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198218	SCV001369088	uncertain significance	Pheochromocytoma	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366184	SCV001562480	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-07-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 825 of the KIF1B protein (p.Glu825Lys). This variant is present in population databases (rs763122049, gnomAD 0.008%). 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: 373920). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KIF1B protein function with a negative predictive value of 80%. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001198218	SCV002526087	uncertain significance	Pheochromocytoma	2021-12-22	criteria provided, single submitter	clinical testing	The KIF1B c.2473G>A (p.Glu825Lys) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-10384889-G-A). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in one individual with Charcot-Marie-Tooth disease Type 2 (PMID: 26392352). To our knowledge, this variant has not been reported in individuals with pheochromocytoma or neuroblastoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4, PP2.
Ambry Genetics	RCV004022180	SCV002734597	uncertain significance	not specified	2023-02-04	criteria provided, single submitter	clinical testing	The p.E825K variant (also known as c.2473G>A), located in coding exon 23 of the KIF1B gene, results from a G to A substitution at nucleotide position 2473. The glutamic acid at codon 825 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.