Submissions for variant NM_000155.4(GALT):c.197C>T (p.Pro66Leu)

gnomAD frequency: 0.00004  dbSNP: rs111033656

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000022066	SCV000952788	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-11-03	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 66 of the GALT protein (p.Pro66Leu). This variant is present in population databases (rs111033656, gnomAD 0.009%). This missense change has been observed in individual(s) with a positive newborn screening result for GALT-related disease (PMID: 25087612; Invitae). ClinVar contains an entry for this variant (Variation ID: 25136). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194273	SCV001363668	uncertain significance	not specified	2019-02-15	criteria provided, single submitter	clinical testing	Variant summary: GALT c.197C>T (p.Pro66Leu) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain 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-05 in 277122 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GALT causing Galactosemia (4e-05 vs 0.0029), allowing no conclusion about variant significance. A publication reports a compound heterozygote patient (Shin 2004), who carried the variant c.197C>A that would cause a missense change of Pro66His however, in the report a missense change of Pro66Leu is indicated. Authors do not provide sequence data therefore it remains unclear whether it is the variant of interest that was reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. However, another well-established clinical diagnostic laboratory, ARUP, has classified the variant as pathogenic prior to 2014. Furthermore, another variant, c.197C>A, affecting the same nucleotide but causing a different missense change, Pro66His has been reported in ClinVar, along with additional variants affecting nearby residues, p.R67C, p.R67H, p.H68P, suggesting the region is important for GALT function. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Myriad Genetics, Inc.	RCV000022066	SCV002060339	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-10-01	criteria provided, single submitter	clinical testing	NM_000155.3(GALT):c.197C>T(P66L) is a missense variant classified as a variant of uncertain significance in the context of galactosemia. P66L has not been observed in cases with relevant disease. Functional assessments of this variant are available in the literature (PMID: 31267113). P66L has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000155.3(GALT):c.197C>T(P66L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Mayo Clinic Laboratories, Mayo Clinic	RCV000767307	SCV004224247	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing	PP3, PM2
Seelig Lab, University of Washington	RCV000767307	SCV000897871	not provided	not provided		no assertion provided	in vitro
Natera, Inc.	RCV001276262	SCV001462311	uncertain significance	Galactosemia	2020-09-16	no assertion criteria provided	clinical testing