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

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

12
3
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 9.15
Variant links:
Genes affected
GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959
PP5
Variant 9-34648850-G-A is Pathogenic according to our data. Variant chr9-34648850-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GALTNM_000155.4 linkc.776G>A p.Arg259Gln missense_variant Exon 8 of 11 ENST00000378842.8 NP_000146.2 P07902-1B2RAT6A0A0S2Z3Y7
GALTNM_001258332.2 linkc.449G>A p.Arg150Gln missense_variant Exon 6 of 9 NP_001245261.1 P07902-2B2RAT6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GALTENST00000378842.8 linkc.776G>A p.Arg259Gln missense_variant Exon 8 of 11 1 NM_000155.4 ENSP00000368119.4 P07902-1
ENSG00000258728ENST00000556278.1 linkc.432+394G>A intron_variant Intron 4 of 7 5 ENSP00000451792.1 G3V4G9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461038
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726878
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:6Uncertain:1
Jul 15, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jun 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 13, 2019
Counsyl
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 01, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jun 10, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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 -

not provided Pathogenic:2
Jun 17, 2018
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jul 05, 2017
Eurofins Ntd Llc (ga)
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Galactosemia Pathogenic:1
Sep 06, 2017
Natera, Inc.
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
.;D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
.;M
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-2.6
D;N
REVEL
Pathogenic
0.92
Sift
Benign
0.52
T;T
Sift4G
Benign
0.15
T;T
Polyphen
1.0
.;D
Vest4
0.88
MutPred
0.83
.;Loss of MoRF binding (P = 0.0599);
MVP
1.0
MPC
1.3
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.48
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886042070; hg19: chr9-34648847; API