rs111033773

chr9-34649032-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:2
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 4 uncertain in NM_000155.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-34649031-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2045110.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 id is 3621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34649032-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALT	NM_000155.4	c.855G>T	p.Lys285Asn	missense_variant	9/11	ENST00000378842.8
GALT	NM_001258332.2	c.528G>T	p.Lys176Asn	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.855G>T	p.Lys285Asn	missense_variant	9/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152180 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251490 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135922

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 SAS 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.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 127 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000319 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:11 Other:2

Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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, Invitae). 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, Invitae). 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). 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: 11152465, 18210213, 25614870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Mar 31, 2020	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 14, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	Most severe classic pathogenic variant in eastern Europe -
not provided, no classification provided	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 09, 2021	- -

Galactosemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.68
MutPred		0.89		.;Loss of ubiquitination at K285 (P = 0.0446);
MVP		0.99
MPC		2.0
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs111033773; hg19: chr9-34649029;