Submissions for variant NM_000155.4(GALT):c.424A>G (p.Met142Val)

dbSNP: rs111033692

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317711	SCV004020475	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: GALT c.424A>G (p.Met142Val) results in a conservative amino acid change located in the N-terminal domain (IPR005849) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251496 control chromosomes. c.424A>G has been reported in the literature in at least one compound heterozygous individual affected with Galactosemia (e.g., Hirokawa_1999). These data suggest the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 11% of normal activity in a COS cell expression system (Hirokawa_1999). The following publication was ascertained in the context of this evaluation (PMID: 10573007). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Additionally, other missense variants affecting the same codon, namely c.425T>A (p.Met142Val) and c.425T>C (p.Met142Thr), have been classified as pathogenic by our lab or reported in ClinVar as pathogenic. Both of these additional missense variants have been reported in the literature in patients affected with galactosemia (PMIDs: 15775761, 25592817, 2011574, 10384398) and studies have found these variants result in <5% GALT activity either experimentally or in erythrocytes from patients harboring these variants (PMIDs: 25592817, 2011574), suggesting this residue is clinically significant. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003317711	SCV004294296	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 142 of the GALT protein (p.Met142Val). For these reasons, this variant has been classified as Pathogenic. 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, 20213376). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GALT function (galactosemia). 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. This missense change has been observed in individual(s) with galactosemia (PMID: 10573007). This variant is not present in population databases (gnomAD no frequency).