Submissions for variant NM_000155.4(GALT):c.602G>A (p.Arg201His)

gnomAD frequency: 0.00003  dbSNP: rs111033735

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723397	SCV000330954	pathogenic	not provided	2015-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022163	SCV000820168	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-02-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the GALT protein (p.Arg201His). This variant is present in population databases (rs111033735, gnomAD 0.02%). This missense change has been observed in individual(s) with galactose-1-phosphate uridyltransferase deficiency which is specific for Duarte or classic galactosemia (PMID: 11397328, 20547145; Invitae). ClinVar contains an entry for this variant (Variation ID: 25227). 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: 11152465). This variant disrupts the p.Arg201 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 22461411), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000022163	SCV001163241	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022163	SCV002041495	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-11-09	criteria provided, single submitter	clinical testing	Variant summary: GALT c.602G>A (p.Arg201His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251486 control chromosomes (gnomAD). c.602G>A has been reported in the literature in individuals affected with Galactosemia (examples: Robertson_2000, Webb_2003, Ko_2010, and Welsink-Karssies_2020). At least one publication reports experimental evidence evaluating an impact on protein function (Welsink-Karssies_2020). GALT enzyme activity in cells obtained from a homozygous individual with this variant was <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000022163	SCV002049032	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-07-19	criteria provided, single submitter	clinical testing	The GALT c.602G>A; p.Arg201His variant (rs111033735) is reported in the literature in individuals with galactosemia (Elsas 1995), including in an individual who is homozygous for the variant (Welsink-Karssies 2020), as well as an individual compound heterozygous with the Duarte allele (Ko 2010). This variant is also reported in ClinVar (Variation ID: 25227). Functional studies of the variant protein have shown a mild decrease in GALT activity compared to wild type protein (Riehman 2001, Ko 2010), but GALT activity in patient erythrocytes carrying the p.Arg201His variant is more pronounced (Ko 2010, Welsink-Karssies 2020). This variant is found in the general population with a low overall allele frequency of 0.002% (7/282866 alleles) in the Genome Aggregation Database. The arginine at codon 201 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.738). Additionally, other variants at this codon (Arg201Cys, Arg201Ser) have been reported in association with galactosemia (see ClinVar Variation ID: 25226, Crespo 2020), giving further support for the importance of this codon for proper GALT function. Based on available information, the p.Arg201His variant is considered to be pathogenic. REFERENCES Crespo C et al. Molecular analysis of GALT gene in Argentinian population: Correlation with enzyme activity and characterization of a novel Duarte-like allele. Mol Genet Metab Rep. 2020 Dec 10;25:100695. PMID: 33335841. Elsas LJ et al. Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes. Am J Hum Genet. 1995 Mar;56(3):630-9. PMID: 7887416. Ko DH et al. Molecular and biochemical characterization of the GALT gene in Korean patients with galactose-1-phosphate uridyltransferase deficiency. Clin Chim Acta. 2010 Oct 9;411(19-20):1506-10. PMID: 20547145. Riehman K et al. Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2001 Apr 6;276(14):10634-40. PMID: 11152465. Welsink-Karssies MM et al. The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes. Mol Genet Metab. 2020 Mar;129(3):171-176. PMID: 31954591.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001831598	SCV002818187	pathogenic	Galactosemia	2024-10-04	criteria provided, single submitter	research	PS3,PM3,PM2,PM5,PP3
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000022163	SCV004806672	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000022163	SCV000796864	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-01-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831598	SCV002085220	pathogenic	Galactosemia	2017-03-16	no assertion criteria provided	clinical testing