Submissions for variant NM_001365951.3(KIF1B):c.1594C>G (p.Pro532Ala)

gnomAD frequency: 0.00013  dbSNP: rs201500946

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527411	SCV000657735	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 486 of the KIF1B protein (p.Pro486Ala). This variant is present in population databases (rs201500946, gnomAD 0.03%). 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: 476778). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF1B protein function. 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	RCV001173593	SCV001336692	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004024379	SCV002695888	likely benign	not specified	2020-06-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV003485606	SCV003814565	uncertain significance	Charcot-Marie-Tooth disease type 2A1	2019-07-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003133359	SCV004032550	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	KIF1B: PP3
PreventionGenetics, part of Exact Sciences	RCV004742497	SCV005350532	uncertain significance	KIF1B-related disorder	2024-07-17	no assertion criteria provided	clinical testing	The KIF1B c.1456C>G variant is predicted to result in the amino acid substitution p.Pro486Ala. This variant has been reported in two individuals with Charcot-Marie-Tooth disease (Supplementary Table 2. Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD, which may be too common to be a primary cause of disease. This variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/476778/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.