9-34649032-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000155.4(GALT):c.855G>T(p.Lys285Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,614,162 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K285T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 1.86

Publications

87 publications found

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 Gene-Disease associations (from GenCC):

classic galactosemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
galactosemia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

GALT links:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000155.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-34649031-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2045110.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 104 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 0.91493 (below the threshold of 3.09). Trascript score misZ: 1.8645 (below the threshold of 3.09). GenCC associations: The gene is linked to galactosemia, classic galactosemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.854

PP5

Variant 9-34649032-G-T is Pathogenic according to our data. Variant chr9-34649032-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3621.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.855G>T	p.Lys285Asn	missense_variant	Exon 9 of 11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2 link	c.528G>T	p.Lys176Asn	missense_variant	Exon 7 of 9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 link	c.855G>T	p.Lys285Asn	missense_variant	Exon 9 of 11	1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1 link	c.432+576G>T		intron_variant	Intron 4 of 7	5		ENSP00000451792.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251490

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000217

AC:

241

AN:

1112010

Other (OTH)

AF:

0.000132

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000292

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:14Other:1

Oct 16, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 31, 2020

Breda Genetics srl

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant c.855G>T (p.Lys285Asn) is reported as pathogenic for galactosemia in ClinVar (Variation ID: 3621) and as affecting function/effect unknown in the Global Variome shared LOVD database v.3.0. In one study, this variant has been identified in homozygous state in 3 unrelated children and in compound heterozygous state with a second mutation in 12 children with classical galactosemia from unrelated families. The cohort of patients included families from Austria, Croatia and Germany. GALT activity in erythrocyte lysates of the three homozygous patients was reduced to 0.5 +- 2.41 mmol/hr/gHb (mean +- SD, normal 27.8 +- 6 mmol/hr/g Hb). The mean GALT activity determined in compound heterozygous patients was 0.5 +- 0.43 mmol/ hr/gHb (mean +- SD). In both homozygotes and compound heterozygotes, the clinical course in the newborn period was severe including jaundice, hepatomegaly, failure to thrive, cataracts, neurological symptoms, and cerebral edema. For most of them intensive care, including exchange transfusions, was necessary. According to the authors, this variant is a common mutation in their population (Greber-Platzer et al., 1997, PMID: 9222760). The variant is reported with an estimated allele frequency of 0.0002 in 1000 Genomes Project, 0.0001392 in gnomAD exomes, and 0.00003186 in gnomAD genomes, with no homozygous individuals reported.

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

Mar 21, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Sep 08, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 12, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003621 /PMID: 1427861 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 25268296). Different missense changes at the same codon (p.Lys285Arg, p.Lys285Thr) have been reported to be associated with GALT related disorder (ClinVar ID: VCV002045110 /PMID: 23022339). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 285 of the GALT protein (p.Lys285Asn). This variant is present in population databases (rs111033773, gnomAD 0.02%). This variant has been observed in individuals with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 18210213, 25592817, 16540753, internal data). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with galactose-1-phosphate uridylyltransferase deficiency (PMID: 25592817, 16540753, internal data). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 3621). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11152465, 18210213, 25614870). For these reasons, this variant has been classified as Pathogenic.

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Most severe classic pathogenic variant in eastern Europe

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 14, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 14, 2023

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GALT c.855G>T (p.Lys285Asn) missense variant is a well-established disease-causing variant which has been reported in many individuals with galactosemia in the peer-reviewed literature (GeneReviews PMID: 20301691). Functional studies and computational evidence support the variant's damaging effect on the GALT enzyme (PMID: 9222760). The highest frequency of this allele in the Genome Aggregation Database is 0.000338 in the European (non-Finnish) population (version 3.1.2). The c.855G>T variant has been classified as pathogenic by over 15 submitters in ClinVar. This variant was identified in trans with a likely pathogenic variant. Based on the available evidence, the c.855G>T (p.Lys285Asn) variant is classified as pathogenic for galactosemia.

Aug 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GALT c.855G>T; p.Lys285Asn variant (rs111033773) is reported in multiple individuals diagnosed with classic galactosemia when found in trans with another pathogenic variant (Chhay 2008, Viggiano 2015). Functional characterization of the variant protein in red blood cells and yeast cells indicates severe reduction in GALT activity (Chhay 2008, Coelho 2014, Viggiano 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 3621). It is found in the general population with an overall allele frequency of 0.01% (36/282874 alleles) in the Genome Aggregation Database. The lysine at codon 285 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.883). Based on available information, the variant is considered to be pathogenic. References: Chhay J et al. A yeast model reveals biochemical severity associated with each of three variant alleles of galactose-1P uridylyltransferase segregating in a single family. J Inherit Metab Dis. 2008; 31(1):97-107. PMID: 18210213. Coelho A et al. Functional and structural impact of the most prevalent missense mutations in classic galactosemia. Mol Genet Genomic Med. 2014; 2(6):484-96. PMID: 25614870. Viggiano E et al. Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene. Gene. 2015; 559(2):112-8. PMID: 25592817.

Nov 11, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000155.3(GALT):c.855G>T(K285N) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 10649501, 9222760, 11152465, and 18210213. Classification of NM_000155.3(GALT):c.855G>T(K285N) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Jan 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:8

Aug 05, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 12, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 17, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Second most common galactosemia-associated variant among people of European ancestry (Tyfield et al., 1999); Published functional studies demonstrate a damaging effect with absent GALT enzyme activity in purified recombinant human protein studies and when expressed in yeast (Coelho et al., 2014; Riehman et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10220154, 25087612, 22975760, 11152465, 18210213, 25614870, 20008339, 21228398, 1427861, 11754113, 10408771, 16540753, 9222760, 10399107, 25592817, 10649501, 29252199, 30994193, 31194252, 31954591, 31980526, 34030713, 31589614)

Sep 14, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GALT: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting

Nov 10, 2023

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the GALT gene demonstrated a sequence change, c.855G>T, in exon 9 that results in an amino acid change, p.Lys285Asn. The p.Lys285Asn change affects a highly conserved amino acid residue located in a domain of the GALT protein that is known to be functional. The p.Lys285Asn substitution appears to be deleterious/possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple unrelated individuals with GALT-related galactosemia (PMID: 16540753, 9222760, 25592817, 20301691). This sequence change has been described in the gnomAD database with a frequency of 0.02% in the European (non-Finnish) subpopulation (dbSNP rs111033773) and is considered one of the most common galactosemia-associated variants in the European population. Biochemical assays of galactosidase activity in individuals with the p.Lys285Asn sequence change demonstrate severely reduced enzyme activity versus wild-type GALT (PMID: 9222760, 25592817). Collectively, this evidence indicates that this sequence change is pathogenic.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Jun 06, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.855G>T (p.K285N) alteration is located in exon 9 (coding exon 9) of the GALT gene. This alteration results from a G to T substitution at nucleotide position 855, causing the lysine (K) at amino acid position 285 to be replaced by an asparagine (N). Based on data from gnomAD, this allele has an overall frequency of 0.013% (36/282874) total alleles studied. The highest observed frequency was 0.025% (9/35440) of Latino alleles. This variant has been identified in the homozygous state and/or in conjunction with other GALT variants in individuals with features consistent with classic as well as Duarte galactosemia; in at least one instance, the variants were identified in trans (Crespo, 2020; Jezela-Stanek, 2021; Forte, 2023). This amino acid position is well conserved in available vertebrate species. In multiple assays testing GALT function, this variant showed functionally abnormal results (Riehman, 2001; Chhay, 2008; Coelho, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Galactosemia

Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;H

PhyloP100

1.9

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Vest4

0.68

ClinPred

0.95

GERP RS

4.7

Varity_R

0.96

gMVP

0.98

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over