Submissions for variant NM_000155.4(GALT):c.974C>T (p.Pro325Leu)

gnomAD frequency: 0.00001  dbSNP: rs111033794

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022250	SCV000755884	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 325 of the GALT protein (p.Pro325Leu). This variant is present in population databases (rs111033794, gnomAD 0.008%). This missense change has been observed in individual(s) with galactosemia (PMID: 9222760, 10573007, 20008339, 20213376, 22944367). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25305). 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%. Experimental studies have shown that this missense change affects GALT function (PMID: 10573007). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000022250	SCV000798721	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-03-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091819	SCV001248042	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022250	SCV001363671	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: GALT c.974C>T (p.Pro325Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR005850) 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 1.2e-05 in 251468 control chromosomes (gnomAD). c.974C>T has been reported in the literature in homozygous- and compound heterozygous state in multiple individuals affected with Galactosemia (e.g. Greber-Platzer_1997, Hirokawa_1999, Gort_2006, Milankovics_2010, Li_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated reduced GALT activity (~11% compared to the WT control) in a cell line transfected with the variant (Hirokawa_1999). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000022250	SCV002024163	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-09-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022250	SCV004198506	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-09-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001091819	SCV004226602	pathogenic	not provided	2023-01-25	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PS3, PS4_moderate
Natera, Inc.	RCV001826502	SCV002085250	pathogenic	Galactosemia	2017-11-29	no assertion criteria provided	clinical testing