Submissions for variant NM_004523.4(KIF11):c.193A>G (p.Thr65Ala)

gnomAD frequency: 0.00009  dbSNP: rs200410468

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237555	SCV001410319	uncertain significance	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 65 of the KIF11 protein (p.Thr65Ala). This variant is present in population databases (rs200410468, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KIF11-related conditions. ClinVar contains an entry for this variant (Variation ID: 963518). 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 KIF11 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.
Baylor Genetics	RCV001331252	SCV001523251	uncertain significance	Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability	2020-02-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV001819934	SCV002069256	uncertain significance	not specified	2021-11-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the KIF11 gene demonstrated a sequence change, c.193A>G, in exon 2 that results in an amino acid change, p.Thr65Ala. This sequence change has been described in the gnomAD database with a frequency of 0.036% in the Latino/admixed American subpopulation (dbSNP rs200410468). The p.Thr65Ala change affects a moderately conserved amino acid residue located in a domain of the KIF11 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr65Ala substitution. This sequence change does not appear to have been previously described in individuals with KIF11-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr65Ala change remains unknown at this time.
Ambry Genetics	RCV002563892	SCV003728764	likely benign	Inborn genetic diseases	2022-06-28	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.
Breakthrough Genomics, Breakthrough Genomics	RCV001237555	SCV005190921	uncertain significance	not provided		criteria provided, single submitter	not provided