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

gnomAD frequency: 0.00001  dbSNP: rs111033694

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the GALT protein (p.Arg148Gln). This variant is present in population databases (rs111033694, gnomAD 0.01%). This missense change has been observed in individuals with galactosemia (PMID: 7887416, 15841485, 19375122, 22944367). ClinVar contains an entry for this variant (Variation ID: 25178). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 25614870). 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: 1373122, 7887416, 15841485, 22944367, 25268296). 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.
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)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000022114	SCV002769257	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_000155.3(GALT):c.443G>A in exon 5 of 11 of the GALT gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 148 of the protein, NP_000146.2(GALT):p.(Arg148Gln). The arginine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the GalP_UDP_transf functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). The variant has been previously reported pathogenic in multiple patients with galactosemia (ClinVar, Boutron, A. et al . (2012), Gort, L. et al . (2006)). In addition, functional studies show that this variant results in null enzyme activity (Coelho, A. I. et al. (2014)). Different variants in the same codon resulting in changes to tryptophan, glycine and proline have also been shown to cause galactosemia (ClinVar, Barbouth, D. S. et al. (2007)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Natera, Inc.	RCV001826492	SCV002085208	pathogenic	Galactosemia	2017-03-17	no assertion criteria provided	clinical testing