NM_000155.4(GALT):c.292G>C (p.Asp98His) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 1, 2025
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:: RCV000022080.28

Allele description [Variation Report for NM_000155.4(GALT):c.292G>C (p.Asp98His)]

NM_000155.4(GALT):c.292G>C (p.Asp98His)

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.292G>C (p.Asp98His)

HGVS:

NC_000009.12:g.34647531G>C
NG_009029.2:g.5943G>C
NG_028966.1:g.347G>C
NM_000155.4:c.292G>CMANE SELECT
NM_001258332.2:c.50+273G>C
NP_000146.2:p.Asp98His
NP_000146.2:p.Asp98His
NC_000009.11:g.34647528G>C
NM_000155.2:c.292G>C
NM_000155.3:c.292G>C

Links:

dbSNP: rs111033670

NCBI 1000 Genomes Browser:

rs111033670

Molecular consequence:

NM_001258332.2:c.50+273G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000155.4:c.292G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Synonyms:: GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY; Transferase Deficiency Galactosemia; GALACTOSEMIA I; 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
SCV000695687	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15172000, 20008339, 1766867 Citation Link,
SCV000755879	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 1, 2025)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14728988, 31395954, 10408771, 12595586, 22743281, 28492532
SCV001163232	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 15, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060377	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Oct 27, 2021)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27308838, 31395954, 14728988, 21228398 Citation Link,
SCV005675401	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Extended [13C]galactose oxidation studies in patients with galactosemia.

Berry GT, Reynolds RA, Yager CT, Segal S.

Mol Genet Metab. 2004 Jun;82(2):130-6.

PubMed [citation]

PMID:: 15172000

Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach.

Facchiano A, Marabotti A.

Protein Eng Des Sel. 2010 Feb;23(2):103-13. doi: 10.1093/protein/gzp076. Epub 2009 Dec 11.

PubMed [citation]

PMID:: 20008339

See all PubMed Citations (12)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695687.2

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

Description

Variant summary: GALT c.292G>C (p.Asp98His) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain (IPR005849) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Moreover, another variant affecting the same residue, p.Asp98Asn has been reported to be associated with galactosemia indicating the variant to be located in a mutational hotspot and the clinical importance of the Asp98 residue. The variant allele was found at a frequency of 4e-06 in 251508 control chromosomes. c.292G>C has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Galactosemia (example, Berry_2004, Reichardt_1991). These data indicate that the variant is very likely to be associated with disease. It was reported in patients with hereditary galactosemia and proven reduced enzyme activity (less than 10% of the WT enzyme) suggesting pathogenicity (unpublished finding). The following publications have been ascertained in the context of this evaluation (PMID: 15172000, 1766867). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000755879.5

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 98 of the GALT protein (p.Asp98His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with galactosemia (PMID: 14728988, 31395954). ClinVar contains an entry for this variant (Variation ID: 25149). 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 80%. 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.Asp98 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10408771, 12595586, 22743281). 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 Baylor Genetics, SCV001163232.2

#	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 Myriad Genetics, Inc., SCV002060377.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_000155.3(GALT):c.292G>C(D98H) is a missense variant classified as likely pathogenic in the context of galactosemia. D98H has been observed in cases with relevant disease (PMID: 21228398, 27308838, 14728988, 31395954). Functional assessments of this variant are not available in the literature. D98H has been observed in population frequency databases (ExAC: OTH 0.11%). In summary, NM_000155.3(GALT):c.292G>C(D98H) 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, SCV005675401.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 3, 2025

ClinVar

Relating variation to medicine