NM_000155.4:c.442C>T

Variant names:

• chr9-34647896-C-T
• rs111033693
• NM_000155.4:c.442C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000155.4(GALT):​c.442C>T​(p.Arg148Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,461,890 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. R148Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.02
• Publications: 13 publications found

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

ENSG00000258728 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000155.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-34647897-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 25178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.985
• PP5: Variant 9-34647896-C-T is Pathogenic according to our data. Variant chr9-34647896-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37359.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	c.442C>T	p.Arg148Trp	missense_variant	Exon 5 of 11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.115C>T	p.Arg39Trp	missense_variant	Exon 3 of 9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.442C>T	p.Arg148Trp	missense_variant	Exon 5 of 11	1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.253-219C>T		intron_variant	Intron 2 of 7	5		ENSP00000451792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251494 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000322 AC: 47 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000804 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:7

Dec 24, 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 tryptophan, which is neutral and slightly polar, at codon 148 of the GALT protein (p.Arg148Trp). This variant is present in population databases (rs111033693, gnomAD 0.02%). This missense change has been observed in individual(s) with galactosemia (PMID: 1373122, 14518827, 22944367). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 37359). 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: 1373122). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg148 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15986423, 17221873, 23151865, 25936995). 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. -

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.442C>Tp.Arg148Trp in the GALT gene which is located in a mutational hot spot has been reported in compound heterozygous state in individuals affected with galactosemia, found in trans with another GALT pathogenic variant Yuzyuk et al., 2018; Boutron et al., 2012. Functional characterization indicates that the variant protein is unstable, resulting in a decrease in steady-state levels and overall GALT activity Reichardt et al., 1992. Different amino acid change affecting codon 148 p.Arg148Gln is reported as a known pathogenic variant. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg148Trp in GALT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Jun 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GALT c.442C>T; p.Arg148Trp variant (rs111033693) has been reported in individuals diagnosed with galactosemia, found in-trans with another GALT pathogenic variant (Boutron 2012, Reichardt 1992). Functional characterization indicates that the variant protein is unstable, resulting in a decrease in steady state levels and overall GALT activity (Reichardt 1992). Other missense variants at this position (p.Arg148Gly and p.Arg148Gln) have also been implicated in galactosemia (Facchiano 2010). The p.Arg148Trp variant is listed as pathogenic in ClinVar (Variation ID: 37359), and observed 8 times in the Genome Aggregation Database general population database (8/282890 alleles). The arginine at residue 148 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, the variant is classified as pathogenic. References: Boutron A et al. Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations. Mol Genet Metab. 2012; 107(3):438-47. Facchiano A et al. Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. Protein Eng Des Sel. 2010; 23(2):103-13. Reichardt J et al. Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia. Genomics. 1992; 12(3):596-600. -

Mar 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GALT c.442C>T (p.Arg148Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251494 control chromosomes. c.442C>T has been reported in the literature in individuals affected with Galactosemia (Berry_2000, Bosch_2005, Reichardt_1992, Schadewaldt_2014). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.443G>A, p.Arg148Gln), supporting the critical relevance of codon 148 to GALT protein function. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Reichardt_1992, Schadewaldt_2014). The following publications have been ascertained in the context of this evaluation (PMID: 15841485, 1373122, 10960497, 25268296). ClinVar contains an entry for this variant (Variation ID: 37359). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

May 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2_moderate, PM5, PS3, PS4_moderate -

Mar 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on enzyme activity (Reichardt et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10960497, 20008339, 15841485, 10408771, 14518827, 1373122, 22944367) -

May 16, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 31, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.442C>T (p.R148W) alteration is located in exon 5 (coding exon 5) of the GALT gene. This alteration results from a C to T substitution at nucleotide position 442, causing the arginine (R) at amino acid position 148 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (8/282890) total alleles studied. The highest observed frequency was 0.016% (5/30616) of South Asian alleles. This variant has been identified in the homozygous state and/or in conjunction with other GALT variants in individuals with features consistent with galactosemia (Reichardt, 1992; Schadewaldt, 2003; Boutron, 2012; Almenabawy, 2024). This amino acid position is highly conserved in available vertebrate species. In an assay testing GALT function, this variant showed a functionally abnormal result (Reichardt, 1992). 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

Nov 15, 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;M
PhyloP100		2.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.015	D;T
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.90		.;Gain of catalytic residue at R148 (P = 0.0379);
MVP		1.0
MPC		1.8
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.89
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111033693; hg19: chr9-34647893; COSMIC: COSV108227021; COSMIC: COSV108227021;