Submissions for variant NM_005546.4(ITK):c.1282C>A (p.Gln428Lys)

gnomAD frequency: 0.00009  dbSNP: rs150270557

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794655	SCV000934076	uncertain significance	Lymphoproliferative syndrome 1	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 428 of the ITK protein (p.Gln428Lys). This variant is present in population databases (rs150270557, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ITK-related conditions. ClinVar contains an entry for this variant (Variation ID: 641419). 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 ITK 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.
Illumina Laboratory Services, Illumina	RCV000794655	SCV001312425	uncertain significance	Lymphoproliferative syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV001816849	SCV002070350	uncertain significance	not specified	2021-11-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ITK gene demonstrated a sequence change, c.1282C>A, in exon 13 that results in an amino acid change, p.Gln428Lys. This sequence change has been described in the gnomAD database with a frequency of 0.026% in the South Asian subpopulation (dbSNP rs150270557). The p.Gln428Lys change affects a moderately conserved amino acid residue located in a domain of the ITK protein that is known to be functional. The p.Gln428Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with ITK-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gln428Lys change remains unknown at this time.