Submissions for variant NM_000154.2(GALK1):c.267G>T (p.Gln89His)

gnomAD frequency: 0.00006  dbSNP: rs144915547

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001126561	SCV001285776	uncertain significance	Deficiency of galactokinase	2018-01-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001126561	SCV003257211	uncertain significance	Deficiency of galactokinase	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 89 of the GALK1 protein (p.Gln89His). This variant is present in population databases (rs144915547, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GALK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 891334). 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 GALK1 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.
Ambry Genetics	RCV002556756	SCV003760101	uncertain significance	Inborn genetic diseases	2024-09-10	criteria provided, single submitter	clinical testing	The c.267G>T (p.Q89H) alteration is located in exon 2 (coding exon 2) of the GALK1 gene. This alteration results from a G to T substitution at nucleotide position 267, causing the glutamine (Q) at amino acid position 89 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.