ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.776G>A (p.Arg259Gln) (rs886042070)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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.
Invitae RCV000319697 SCV001218051 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 259 of the GALT protein (p.Arg259Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with galactosemia (PMID: 22461411). ClinVar contains an entry for this variant (Variation ID: 280989). This variant has been reported to affect GALT protein function (PMID: 22461411). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000319697 SCV000800590 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-03-13 no assertion criteria provided clinical testing

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