Submissions for variant NM_000155.4(GALT):c.552C>A (p.His184Gln)

dbSNP: rs111033717

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493954	SCV000582003	likely pathogenic	not provided	2016-09-07	criteria provided, single submitter	clinical testing	The H184Q variant in the GALT gene has been reported previously in patients with galactosemia (Tyfield et al. 1999; Yang et al. 2002). The H184Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H184Q variant is a semi-conservative amino acid substitution. The H184Q variant occurs at a position within the catalytic site of the galactose 1-phosphate uridyltransferase protein that is conserved across species (Elsas et al. 1998). In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret H184Q as being likely pathogenic.
Counsyl	RCV000022146	SCV000800628	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2017-11-27	criteria provided, single submitter	clinical testing
Invitae	RCV000022146	SCV002234863	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 184 of the GALT protein (p.His184Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic galactosemia (PMID: 10535394, 11397328). ClinVar contains an entry for this variant (Variation ID: 25210). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022146	SCV002547872	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-05-09	criteria provided, single submitter	clinical testing	Variant summary: GALT c.552C>A (p.His184Gln) 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 was absent in 251476 control chromosomes. c.552C>A has been reported in the literature in individuals affected with Galactosemia (example, Palmieri_1999, Yang_2002, Berry_2004, Robertson_2000). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic/Likely Pathogenic, n=3; VUS, n=1). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000022146	SCV004198498	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-10-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000493954	SCV004226591	pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3_strong, PS4_moderate
Natera, Inc.	RCV001835632	SCV002085216	likely pathogenic	Galactosemia	2020-08-14	no assertion criteria provided	clinical testing