Submissions for variant NM_000155.4(GALT):c.221T>C (p.Leu74Pro)

dbSNP: rs111033663

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723459	SCV000700444	pathogenic	not provided	2017-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003799	SCV001437257	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-09-24	criteria provided, single submitter	clinical testing	Variant summary: GALT c.221T>C (p.Leu74Pro) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251302 control chromosomes. c.221T>C has been reported in the literature in at least one individual affected with Galactosemia (Reichardt_1992). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Reichardt_1992, McCorvie_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000003799	SCV003835281	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-11-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000723459	SCV004226582	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3, PS3
GeneDx	RCV000723459	SCV005079064	pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Functional studies resulted in no GALT enzyme activity when L74P was over-expressed in COS cells and yeast cells (PMID: 1610789, 23583749); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20008339, 1301925, 23583749, 1610789, 7887416, 23891399, 7671959, 10408771, 11261429)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003799	SCV005835679	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 74 of the GALT protein (p.Leu74Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic galactosemia (PMID: 1610789, 7887416, 30718057). ClinVar contains an entry for this variant (Variation ID: 3615). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 1610789, 23583749). 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.
OMIM	RCV000003799	SCV000023964	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	1992-06-23	no assertion criteria provided	literature only
Natera, Inc.	RCV001826411	SCV002085186	likely pathogenic	Galactosemia	2020-02-02	no assertion criteria provided	clinical testing