rs111033792

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000155.4(GALT):c.957C>A(p.His319Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,040 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: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.291

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]

GALT links:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

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, 0.994

PP5

Variant 9-34649462-C-A is Pathogenic according to our data. Variant chr9-34649462-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3617.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
GALT	NM_000155.4 link	c.957C>A	p.His319Gln	missense_variant	Exon 10 of 11	ENST00000378842.8	NP_000146.2	P07902-1B2RAT6A0A0S2Z3Y7
GALT	NM_001258332.2 link	c.630C>A	p.His210Gln	missense_variant	Exon 8 of 9		NP_001245261.1	P07902-2B2RAT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 link	c.957C>A	p.His319Gln	missense_variant	Exon 10 of 11	1	NM_000155.4	ENSP00000368119.4		P07902-1
ENSG00000258728	ENST00000556278.1 link	c.432+1006C>A		intron_variant	Intron 4 of 7	5		ENSP00000451792.1		G3V4G9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251456

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:6

Jul 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 319 of the GALT protein (p.His319Gln). This variant is present in population databases (rs111033792, gnomAD 0.0009%). This missense change has been observed in individual(s) with galactose-1-phosphate uridylyltransferase deficiency (PMID: 8499924, 8956044, 22944367, 23022339, 25268296). ClinVar contains an entry for this variant (Variation ID: 3617). 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: 8499924). For these reasons, this variant has been classified as Pathogenic. -

Nov 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GALT c.957C>A (p.His319Gln) variant has been reported in four patient studies in which it is identified in a total of six individuals with galactosemia, including one in a homozygous state, three in a compound heterozygous state, and two in a heterozygous state without a second identified variant (Reichardt et al., 1993; Maceratesi et al., 1996; Singh et al., 2012; Schadewaldt et al., 2014). The p.His319Gln variant was absent from 178 control alleles and is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele only in an area of good coverage so the variant is presumed to be rare. In a study by Reichardt et al. (1993), expression analysis of the variant in COS7 cells showed undetectable enzyme activity. Further analysis of transfected cells carrying the p.His319Gln variant failed to detect appreciable amounts of protein whilst having a high level of mRNA, suggesting the p.His319Gln variant encodes an unstable polypeptide. The residue resides in a domain that is conserved in E.coli and yeast and is located in the metal binding site of GALT (McCorvie et al. 2016). Schadewalt et al. (2014) and Singh et al. (2012) also found low levels of GALT enzyme activity in patients with the p.His319Gln variant ranging from 18% to less than 1.5% of control levels. Based on the evidence, the p.His319Gln variant is classified as pathogenic for galactosemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:3

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2, PM3, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

.;D

Eigen

Benign

0.084

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.75

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;H

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.8

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.89

MutPred

0.98

.;Loss of helix (P = 0.1299);

MVP

0.98

MPC

0.33

ClinPred

1.0

GERP RS

-2.3

Varity_R

0.98

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over