Submissions for variant NM_000155.4(GALT):c.443G>A (p.Arg148Gln) (rs111033694)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000723398	SCV000230859	pathogenic	not provided	2014-05-27	criteria provided, single submitter	clinical testing
Invitae	RCV000022114	SCV000631392	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 148 of the GALT protein (p.Arg148Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs111033694, ExAC 0.009%). This variant has been reported as homozygous or in combination with other GALT variants in individuals affected with galactosemia (PMID: 7887416, 19375122, 15841485, 22944367). Experimental studies have shown that this missense change drastically reduces GALT enzymatic activity (PMID: 25614870). A different missense substitution at this codon (p.Arg148Trp) has been determined to be pathogenic (PMID: 7887416, 1373122, 15841485, 22944367, 25268296). This suggests that the arginine residue is critical for GALT protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000022114	SCV000789695	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2017-02-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022114	SCV000917420	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-02-12	criteria provided, single submitter	clinical testing	Variant summary: GALT c.443G>A (p.Arg148Gln) results in a conservative amino acid change located in the N-terminal of the Galactose-1-phosphate uridyl transferase, of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246264 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in GALT causing Galactosemia (2.8e-05 vs 2.90E-03), allowing no conclusion about variant significance. The variant, c.443G>A, has been reported in the literature in multiple individuals affected with Galactosemia (Elsas_1995, Bosch_2005, Gort_2009, Boutron_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000022114	SCV001163238	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		criteria provided, single submitter	clinical testing
GeneDx	RCV000723398	SCV001822996	pathogenic	not provided	2019-10-21	criteria provided, single submitter	clinical testing	Expression studies found that the R148Q variant was associated with GALT enzyme activity below the limits of detection (Coelho et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31980526, 7887416, 25614870, 25525159, 20008339)
Research and Development, ARUP Laboratories	RCV000022114	SCV000042792	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.