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

Total submissions: 4

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.
Integrated Genetics/Laboratory Corporation of America	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.
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.