rs886042070
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000155.4(GALT):c.776G>A(p.Arg259Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000155.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461038Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726878
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:6Uncertain:1
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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. -
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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. -
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 -
not provided Pathogenic:2
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. -
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Galactosemia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at