NM_000155.4(GALT):c.443G>A (p.Arg148Gln) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Feb 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000022114.19

Allele description [Variation Report for NM_000155.4(GALT):c.443G>A (p.Arg148Gln)]

NM_000155.4(GALT):c.443G>A (p.Arg148Gln)

Gene:

GALT:galactose-1-phosphate uridylyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_000155.4(GALT):c.443G>A (p.Arg148Gln)

HGVS:

NC_000009.12:g.34647897G>A
NG_009029.2:g.6309G>A
NG_028966.1:g.713G>A
NM_000155.4:c.443G>AMANE SELECT
NM_001258332.2:c.116G>A
NP_000146.2:p.Arg148Gln
NP_001245261.1:p.Arg39Gln
NC_000009.11:g.34647894G>A
NM_000155.2:c.443G>A
NM_000155.3:c.443G>A
P07902:p.Arg148Gln

Protein change:

R39Q

Links:

UniProtKB: P07902#VAR_002578; dbSNP: rs111033694

NCBI 1000 Genomes Browser:

rs111033694

Molecular consequence:

NM_000155.4:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.116G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Synonyms:: GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY; Galactose-1-phosphate uridyltransferase deficiency; Transferase Deficiency Galactosemia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009258; MedGen: C0268151; Orphanet: 352; Orphanet: 79239; OMIM: 230400

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000631392	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19375122, 25614870, 1373122, 7887416, 15841485, 22944367, 25268296, 28492532
SCV000789695	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Feb 10, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11397328, 15841485, 22944367, 19375122, 25614870, 23749220 Citation Link,
SCV000917420	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 12, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10408771, 15841485, 17041746, 19375122, 7671959, 7887416, 22944367 Citation Link,
SCV001163238	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002769257	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17041746, 17957157, 22944367, 25614870, 25741868
SCV004814136	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Dec 20, 2021)	unknown	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia.

Reichardt JK, Belmont JW, Levy HL, Woo SL.

Genomics. 1992 Mar;12(3):596-600.

PubMed [citation]

PMID:: 1373122

Endogenous galactose formation in galactose-1-phosphate uridyltransferase deficiency.

Schadewaldt P, Kamalanathan L, Hammen HW, Kotzka J, Wendel U.

Arch Physiol Biochem. 2014 Dec;120(5):228-39. doi: 10.3109/13813455.2014.962547. Epub 2014 Sep 30.

PubMed [citation]

PMID:: 25268296

See all PubMed Citations (15)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000631392.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the GALT protein (p.Arg148Gln). This variant is present in population databases (rs111033694, gnomAD 0.01%). This missense change has been observed in individuals with galactosemia (PMID: 7887416, 15841485, 19375122, 22944367). ClinVar contains an entry for this variant (Variation ID: 25178). 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: 25614870). 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: 1373122, 7887416, 15841485, 22944367, 25268296). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000789695.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917420.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: GALT c.443G>A (p.Arg148Gln) results in a conservative amino acid change located in the N-terminal of the Galactose-1-phosphate uridyl transferase, of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246264 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in GALT causing Galactosemia (2.8e-05 vs 2.90E-03), allowing no conclusion about variant significance. The variant, c.443G>A, has been reported in the literature in multiple individuals affected with Galactosemia (Elsas_1995, Bosch_2005, Gort_2009, Boutron_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163238.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769257.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

A heterozygous missense variant was identified, NM_000155.3(GALT):c.443G>A in exon 5 of 11 of the GALT gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 148 of the protein, NP_000146.2(GALT):p.(Arg148Gln). The arginine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the GalP_UDP_transf functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). The variant has been previously reported pathogenic in multiple patients with galactosemia (ClinVar, Boutron, A. et al. (2012), Gort, L. et al. (2006)). In addition, functional studies show that this variant results in null enzyme activity (Coelho, A. I. et al. (2014)). Different variants in the same codon resulting in changes to tryptophan, glycine and proline have also been shown to cause galactosemia (ClinVar, Barbouth, D. S. et al. (2007)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV004814136.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The GALT c.443G>A p(.Arg148Gln) missense variant has been identified in individuals with a phenotype consistent with galactosemia, including at least one in a homozygous state and one in a compound heterozygous state (Elsas et al. 1995; Bosch et al. 2005; Gort et al. 2006; Boutron et al. 2012). The highest frequency of this allele in the Genome Aggregation Database is 0.000145 in the Latino/Admixed American population (version 2.1.1). The c.443G>A variant lies within the galactose-1-phosphate uridyl transferase, N-terminal domain, in which multiple missense variants have been previously reported as likely pathogenic or pathogenic for galactosemia. Computational modeling predicts damaging effect of the variant on GALT function, and in vitro studies showed that the p.Arg148Gln change results in undetectable enzyme activity (Facchiano and Marabotti 2010; Coelho et al. 2014). Additionally, an alternative amino acid change at the same position, the p.Arg148Trp, has been reported in individuals affected with galactosemia (Elsas et al. 1995; Bosch et al. 2005; Boutron et al. 2012). Based on the available evidence, the c.443G>A p.(Arg148Gln) variant is classified as pathogenic for galactosemia.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

ClinVar

Relating variation to medicine