NM_000155.4(GALT):c.1049C>A (p.Thr350Asn) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 30, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001001297.15

Allele description [Variation Report for NM_000155.4(GALT):c.1049C>A (p.Thr350Asn)]

NM_000155.4(GALT):c.1049C>A (p.Thr350Asn)

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.1049C>A (p.Thr350Asn)

HGVS:

NC_000009.12:g.34649554C>A
NG_009029.2:g.7966C>A
NG_028966.1:g.2370C>A
NM_000155.4:c.1049C>AMANE SELECT
NM_001258332.2:c.722C>A
NP_000146.2:p.Thr350Asn
NP_001245261.1:p.Thr241Asn
NC_000009.11:g.34649551C>A

Protein change:

T241N

Links:

dbSNP: rs775317639

NCBI 1000 Genomes Browser:

rs775317639

Molecular consequence:

NM_000155.4:c.1049C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.722C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001158477	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (May 16, 2019)	germline	clinical testing	Citation Link,
SCV002290084	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8741038, 11152465, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001158477

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(May 16, 2019)

germline

clinical testing

Citation Link,

SCV002290084

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 30, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

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

Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase.

Riehman K, Crews C, Fridovich-Keil JL.

J Biol Chem. 2001 Apr 6;276(14):10634-40. Epub 2001 Jan 4.

PubMed [citation]

PMID:: 11152465

See all PubMed Citations (3)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158477.1

#	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.1049C>A; p.Thr350Asn variant (rs775317639), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found on a single chromosome (1/246224 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 350 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Thr350Ala) has been reported in an individual with galactosemia, exhibits decreased enzymatic activity, and is considered disease-causing (Riehman 2002, Shin 1996). However, given the lack of clinical and functional data, the significance of the p.Thr350Asn variant is uncertain at this time. References: Riehman K et al. Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2001 Apr 6;276(14):10634-40. Shin YS et al. Three missense mutations in the galactose-1-phosphate uridyltransferase gene of three families with mild galactosaemia. Eur J Pediatr. 1996 May;155(5):393-7.

#	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 Invitae, SCV002290084.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 350 of the GALT protein (p.Thr350Asn). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr350 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8741038, 11152465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 811444). This variant has not been reported in the literature in individuals affected with GALT-related conditions. This variant is present in population databases (rs775317639, gnomAD 0.003%).

#	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

Last Updated: May 12, 2024

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