Submissions for variant NM_000155.4(GALT):c.413C>G (p.Thr138Arg)

dbSNP: rs111033686

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781401	SCV000919400	uncertain significance	not specified	2018-02-21	criteria provided, single submitter	clinical testing	Variant summary: GALT c.413C>G (p.Thr138Arg) results in a non-conservative amino acid change located in the 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 was absent in 277226 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.413C>G in individuals affected with Galactosemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001856196	SCV002298182	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-04-16	criteria provided, single submitter	clinical testing	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 sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 138 of the GALT protein (p.Thr138Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GALT-related conditions. ClinVar contains an entry for this variant (Variation ID: 633233). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Thr138 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887416, 8741038, 11397328, 11754113, 22743281, 22944367). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Natera, Inc.	RCV001276266	SCV001462315	uncertain significance	Galactosemia	2020-09-16	no assertion criteria provided	clinical testing