Submissions for variant NM_001008216.2(GALE):c.449C>T (p.Thr150Met)

gnomAD frequency: 0.00001  dbSNP: rs765353795

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001331200	SCV001537895	pathogenic	UDPglucose-4-epimerase deficiency	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 150 of the GALE protein (p.Thr150Met). This variant is present in population databases (rs765353795, gnomAD 0.05%). This missense change has been observed in individual(s) with GALE-related conditions (PMID: 16385452, 34448047, 36056436, 36395340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1029823). 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 GALE protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GALE function (PMID: 36395340). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV001331200	SCV002600028	likely pathogenic	UDPglucose-4-epimerase deficiency	2022-06-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001331200	SCV003928968	pathogenic	UDPglucose-4-epimerase deficiency	2023-04-24	criteria provided, single submitter	clinical testing	Variant summary: GALE c.449C>T (p.Thr150Met) results in a non-conservative amino acid change located in the NAD(P)-binding domain (IPR016040) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALE causing UDPglucose-4-Epimerase Deficiency (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.449C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with UDPglucose-4-Epimerase Deficiency (Openo_2006, Derks_2022, Perea-Romero_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evaluations of the variant protein have shown contradictory effects of the variant on protein function: protein lysates from lymphoblastoid cell lines generated from a homozygous patient showed 30% residual activity (Openo_2006). However, in a yeast complementation assay, the variant protein could rescue galactose metabolism to levels comparable to cultures rescued with WT protein (Chhay_2008). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001331200	SCV001523188	uncertain significance	UDPglucose-4-epimerase deficiency	2019-09-20	flagged submission	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM	RCV003991510	SCV004809176	pathogenic	Thrombocytopenia 13, syndromic	2024-04-05	no assertion criteria provided	literature only