Submissions for variant NM_000155.4(GALT):c.413C>T (p.Thr138Met)

gnomAD frequency: 0.00003  dbSNP: rs111033686

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV000022107	SCV001193822	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-12-19	criteria provided, single submitter	clinical testing	NM_000155.3(GALT):c.413C>T(T138M) is classified as likely pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 8741038, 17876724, 10960497, 22944367 and 11754113. Classification of NM_000155.3(GALT):c.413C>T(T138M) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022107	SCV001363670	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: GALT c.413C>T (p.Thr138Met) 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 1.2e-05 in 251494 control chromosomes. c.413C>T has been reported in the literature in individuals affected with Galactosemia (examples- Elsas_1995, Shin_1999, Yang_2002, Calderon_2007, Boutron_2012). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. At least two studies report that the variant retains less than 10% of the normal GALT enzymatic activity (examples- Shin_1999, Berry_2000). Two other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022107	SCV001386289	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 138 of the GALT protein (p.Thr138Met). This variant is present in population databases (rs111033686, gnomAD 0.006%). This missense change has been observed in individual(s) with galactosemia (PMID: 7887416, 8741038, 11397328, 11754113, 22743281, 22944367). ClinVar contains an entry for this variant (Variation ID: 25174). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507744	SCV001713483	pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	PP3, PM2
Fulgent Genetics, Fulgent Genetics	RCV000022107	SCV002813904	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-02-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000022107	SCV003825783	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-01-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022107	SCV004198499	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-12	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000022107	SCV005849367	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.413C>T(p.Thr138Met) variant in GALT gene has been reported previously in compound heterozygous/ homozygous state in individuals affected with galactosemia (Pasquali M, et. al., 2018; Pyhtila BM, et. al., 2015; Calderon FR, et. al., 2007; Calderon FR, et. al., 2007). Experimental studies have shown that this variant has disrupted impact on protein function (Berry GT, et. al., 2000). This variant is present with an allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely pathogenic/ Pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict damaging effect on protein structure and function for this variant. The reference amino acid at this position in GALT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 138 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV001831597	SCV002085202	pathogenic	Galactosemia	2017-03-17	no assertion criteria provided	clinical testing