Submissions for variant NM_000155.4(GALT):c.776G>A (p.Arg259Gln)

dbSNP: rs886042070

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723422	SCV000330999	likely pathogenic	not provided	2017-07-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000319697	SCV000695702	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2016-11-01	criteria provided, single submitter	clinical testing	Variant summary: The GALT c.776G>A (p.Arg259Gln) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121330 control chromosomes. This variant has been reported in at least two affected individuals via publications, and multiple clinical laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Functional study showed variant protein with no enzyme activity. Taken together, this variant is classified as likely pathogenic until more evidence becomes available.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723422	SCV000883931	likely pathogenic	not provided	2018-06-17	criteria provided, single submitter	clinical testing	The GALT c.776G>A; p.Arg259Gln variant (rs886042070) has been described in the compound heterozygous state in at least one individual with galactosemia, who has no detectable GALT enzyme activity in their red blood cells (Tang 2012). It is reported as likely pathogenic in ClinVar (Variation ID: 280989) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 259 is highly conserved, but computational algorithms (PolyPhen-2: probably damaging, SIFT: tolerated) are inconclusive on the effect of this variant on protein structure and/or function. Another variant at this codon (c.775C>T; p.Arg259Trp) has been described in individuals with galactosemia and in vitro analysis of this variant protein demonstrates a significant reduction in GALT activity (Riehman 2001, Shin 1996). Based on available information, this variant is considered likely pathogenic. References: 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. Shin Y et al. Three missense mutations in the galactose-1-phosphate uridyltransferase gene of three families with mild galactosaemia. Eur J Pediatr. 1996 May;155(5):393-7. Tang M et al. Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose-1-phosphate uridylyltransferase gene. Hum Mutat. 2012 Jul;33(7):1107-15.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000319697	SCV001218051	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-01	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 259 of the GALT protein (p.Arg259Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with galactosemia (PMID: 22461411). ClinVar contains an entry for this variant (Variation ID: 280989). 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: 22461411). This variant disrupts the p.Arg259 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8741038, 11152465, 23749220). 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.
Mendelics	RCV000319697	SCV002516441	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-05-04	criteria provided, single submitter	clinical testing
DASA	RCV000319697	SCV002526392	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-06-10	criteria provided, single submitter	clinical testing	The c.776G>A;p.(Arg259Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 280989; PMID: 27603904; 23749220; 23418865; 22461411) - PS4. The variant is present at low allele frequencies population databases (rs886042070– gnomAD no frequency%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg259Gln) was detected in trans with a Pathogenic variant (PMID: 23749220; 23418865; 22461411) - PM3. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 189191 - c.775C>T (p.Arg259Trp)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Baylor Genetics	RCV000319697	SCV004198527	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000319697	SCV005675422	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-06-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000319697	SCV000800590	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-03-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001828172	SCV002085236	likely pathogenic	Galactosemia	2017-09-06	no assertion criteria provided	clinical testing