NM_000155.4(GALT):c.775C>T (p.Arg259Trp) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Mar 27, 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:: RCV000169625.18

Allele description [Variation Report for NM_000155.4(GALT):c.775C>T (p.Arg259Trp)]

NM_000155.4(GALT):c.775C>T (p.Arg259Trp)

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.775C>T (p.Arg259Trp)

HGVS:

NC_000009.12:g.34648849C>T
NG_009029.2:g.7261C>T
NG_028966.1:g.1665C>T
NM_000155.4:c.775C>TMANE SELECT
NM_001258332.2:c.448C>T
NP_000146.2:p.Arg259Trp
NP_001245261.1:p.Arg150Trp
NC_000009.11:g.34648846C>T
NM_000155.2:c.775C>T
NM_000155.3:c.775C>T
P07902:p.Arg259Trp

Protein change:

R150W

Links:

UniProtKB: P07902#VAR_002606; dbSNP: rs786204763

NCBI 1000 Genomes Browser:

rs786204763

Molecular consequence:

NM_000155.4:c.775C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.448C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001163244	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001579739	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 20, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8741038, 22944367, 23749220, 25268296, 11152465, 22461411, 28492532
SCV002060215	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 8, 2021)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 8892021, 22944367, 31194895, 23749220, 9396569, 10535394, 27363831, 11152465, 21779791, 25268296 Citation Link,
SCV002799427	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Three missense mutations in the galactose-1-phosphate uridyltransferase gene of three families with mild galactosaemia.

Shin YS, Gathof BS, Podskarbi T, Sommer M, Giugliani R, Gresser U.

Eur J Pediatr. 1996 May;155(5):393-7.

PubMed [citation]

PMID:: 8741038

Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose-1-phosphate uridylyltransferase gene.

Tang M, Facchiano A, Rachamadugu R, Calderon F, Mao R, Milanesi L, Marabotti A, Lai K.

Hum Mutat. 2012 Jul;33(7):1107-15. doi: 10.1002/humu.22093. Epub 2012 Apr 30.

PubMed [citation]

PMID:: 22461411
PMCID:: PMC3431212

See all PubMed Citations (14)

Details of each submission

From Baylor Genetics, SCV001163244.2

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001579739.4

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 259 of the GALT protein (p.Arg259Trp). This variant is present in population databases (rs786204763, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with galactose-1-phosphate uridyltransferase deficiency (PMID: 8741038, 22944367, 23749220, 25268296). 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: 189191). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 11152465). 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.Arg259 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 22461411), which suggests that this may be a clinically significant amino acid residue. 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 Myriad Genetics, Inc., SCV002060215.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

NM_000155.3(GALT):c.775C>T(R259W) is a missense variant classified as likely pathogenic in the context of galactosemia. R259W has been observed in cases with relevant disease (PMID: 8892021, 10535394, 21779791, 22944367, 25268296, 27363831, 9396569, 31194895, 23749220). Functional assessments of this variant are available in the literature (PMID: 11152465). R259W has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, NM_000155.3(GALT):c.775C>T(R259W) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002799427.1

#	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

Last Updated: Sep 29, 2024

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