Submissions for variant NM_000155.4(GALT):c.425T>C (p.Met142Thr)

dbSNP: rs111033695

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001958767	SCV002240340	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 142 of the GALT protein (p.Met142Thr). This variant is present in population databases (rs111033695, gnomAD 0.0009%). This missense change has been observed in individual(s) with galactosemia (PMID: 25592817). ClinVar contains an entry for this variant (Variation ID: 1458954). 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 expected to disrupt GALT protein function with a positive predictive value of 95%. This variant disrupts the p.Met142 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2011574, 10384398, 10960497, 17041746, 20213376). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001958767	SCV005885846	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2025-02-19	criteria provided, single submitter	clinical testing	Variant summary: GALT c.425T>C (p.Met142Thr) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain (IPR005849) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251496 control chromosomes. c.425T>C has been reported in the literature in at least one compound heterozygous individual affected with GALT deficiency (e.g., Zaffanello_2005). A different variant affecting the same codon has been classified as pathogenic by our lab (c.425T>A, p.Met124Lys), supporting the critical relevance of codon 142 to GALT protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 15775761). ClinVar contains an entry for this variant (Variation ID: 1458954). Based on the evidence outlined above, the variant was classified as likely pathogenic.