Submissions for variant NM_000155.4(GALT):c.442C>T (p.Arg148Trp) (rs111033693)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000414362	SCV000110061	pathogenic	not provided	2018-05-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000414362	SCV000491247	pathogenic	not provided	2016-10-27	criteria provided, single submitter	clinical testing	The R148W missense variant in the GALT gene has been previously reported in patients with galactoemia (Reichardt et al. 1992; Berry et al. 2000; Bosch et al. 2005). Expression of R148W in COS cells found that it is associated with no detectable galactose-1-phosphate uridyltransferase enzyme activity (Reichardt et al. 1992). The R148W 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. R148W is a non-conservative amino acid substitution, it occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, multiple missense variants at the same position (R148Q, R148G) and in nearby residues (S143L, V150L, V151A) are interpreted to be pathogenic variants associated with galactosemia, supporting the functional importance of this region of the protein. In summary, we interpret R148W to be a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022113	SCV000919399	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-01-23	criteria provided, single submitter	clinical testing	Variant summary: The GALT c.442C>T (p.Arg148Trp) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant. This variant was found in 9/277232 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). The variant has been reported in affected individuals in the literature (Berry_2000; Bosch_2005; (Reichardt_1992; Schadewaldt_2014). A functional studies showed the variant to result in nondetectable levels of immunoreactive protein, despite normal levels of mRNA signifying unstable protein (Reichardt_1992; Schadewaldt_2014). Other variants affecting the same codon have been reported as pathogenic [c.442C>G (p.Arg148Gly), c.443G>A (p.Arg148Gly)], further supporting the functional importance of the position. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000022113	SCV001156620	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-11-05	criteria provided, single submitter	clinical testing	The GALT c.442C>T; p.Arg148Trp variant (rs111033693) has been reported in individuals diagnosed with galactosemia, found in-trans with another GALT pathogenic variant (Boutron 2012, Reichardt 1992). Functional characterization indicates that the variant protein is unstable, resulting in a decrease in steady state levels and overall GALT activity (Reichardt 1992). Other missense variants at this position (p.Arg148Gly and p.Arg148Gln) have also been implicated in galactosemia (Facchiano 2010). The p.Arg148Trp variant is listed as pathogenic in ClinVar (Variation ID: 37359), and observed 8 times in the Genome Aggregation Database general population database (8/282890 alleles). The arginine at residue 148 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, the variant is classified as pathogenic. References: Boutron A et al. Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations. Mol Genet Metab. 2012; 107(3):438-47. Facchiano A et al. Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. Protein Eng Des Sel. 2010; 23(2):103-13. Reichardt J et al. Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia. Genomics. 1992; 12(3):596-600.
Invitae	RCV000022113	SCV001589613	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 148 of the GALT protein (p.Arg148Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs111033693, ExAC 0.01%). This variant has been observed in individual(s) with galactosemia (PMID: 1373122, 14518827, 22944367). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 37359). This variant has been reported to affect GALT protein function (PMID: 1373122). This variant disrupts the p.Arg148 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15986423, 23151865, 17221873, 25936995). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories	RCV000022113	SCV000042791	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.