NM_000155.4(GALT):c.292G>A (p.Asp98Asn) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 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:: RCV000022079.29

Allele description [Variation Report for NM_000155.4(GALT):c.292G>A (p.Asp98Asn)]

NM_000155.4(GALT):c.292G>A (p.Asp98Asn)

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>A (p.Asp98Asn)

HGVS:

NC_000009.12:g.34647531G>A
NG_009029.2:g.5943G>A
NG_028966.1:g.347G>A
NM_000155.4:c.292G>AMANE SELECT
NM_001258332.2:c.50+273G>A
NP_000146.2:p.Asp98Asn
NC_000009.11:g.34647528G>A
NM_000155.2:c.292G>A
NM_000155.3:c.292G>A
P07902:p.Asp98Asn

Links:

UniProtKB: P07902#VAR_002560; dbSNP: rs111033670

NCBI 1000 Genomes Browser:

rs111033670

Molecular consequence:

NM_001258332.2:c.50+273G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000155.4:c.292G>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
SCV000833544	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10408771, 12595586, 17876724, 22743281, 28492532
SCV000917410	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 16, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20008339, 12595586, 27005423, 10408771, 28644047 Citation Link,
SCV002053954	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	research	PubMed (1) [See all records that cite this PMID]
SCV002060382	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Oct 22, 2021)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30718057, 28644047, 27363831, 31358168, 17876724, 12595586 Citation Link,
SCV002506308	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Sep 23, 2022)	germline	clinical testing	Citation Link,
SCV002809731	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198492	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 20, 2024)	unknown	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	inherited	yes	not provided	not provided	not provided	not provided	not provided	research
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

N- and O-linked glycosylation of total plasma glycoproteins in galactosemia.

Liu Y, Xia B, Gleason TJ, Castañeda U, He M, Berry GT, Fridovich-Keil JL.

Mol Genet Metab. 2012 Aug;106(4):442-54. doi: 10.1016/j.ymgme.2012.05.025. Epub 2012 Jun 12.

PubMed [citation]

PMID:: 22743281
PMCID:: PMC3426456

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000833544.6

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 98 of the GALT protein (p.Asp98Asn). This variant is present in population databases (rs111033670, gnomAD 0.006%). This missense change has been observed in individual(s) with galactosemia (PMID: 10408771, 12595586, 17876724, 22743281). ClinVar contains an entry for this variant (Variation ID: 25148). 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 80%. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917410.1

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

Description

Variant summary: The GALT c.292G>A (p.Asp98Asn) variant involves the alteration of a conserved nucleotide, is located in UDP-alpha-D-glucose binding region and is involved in interaction with substrate (UniProt, Facchiano_2010). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/277204 control chromosomes (gnomAD) at a frequency of 0.0000289, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). This variant has been reported in multiple patients with galactosemia in homozygous as well as in compound heterozygous state with other pathogenic variants (Tyfield, Webb_2003, Schulpis_2017, ARUP). Enzymatic analysis of the homozygote showed no activity, strongly suggesting that this variant is defective. Another missense change at the same codon (p.Asp98His) has been classified as pathogenic by our lab, suggesting functional importance of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is 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 Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002053954.1

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

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

From Myriad Genetics, Inc., SCV002060382.2

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

Description

NM_000155.3(GALT):c.292G>A(D98N) is a missense variant classified as likely pathogenic in the context of galactosemia. D98N has been observed in cases with relevant disease (PMID: 31358168, 28644047, 17876724, 27363831, 30718057, 12595586). Functional assessments of this variant are not available in the literature. D98N has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000155.3(GALT):c.292G>A(D98N) 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002506308.4

#	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.292G>A; p.Asp98Asn variant (rs111033670), is reported in the compound heterozygous state in the literature in individuals affected with galactosemia (Calderon 2007, Tyfield 1999). This variant is reported in ClinVar (Variation ID: 25148), and found in the general population with an overall allele frequency of 0.003% (10/282870 alleles) in the Genome Aggregation Database. The aspartate at codon 98 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.954). Based on available information, this variant is considered to be pathogenic. References: Calderon FR et al. Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene. J Inherit Metab Dis. 2007 Oct;30(5):818. PMID: 17876724. Tyfield L et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. PMID: 10408771

#	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 Fulgent Genetics, Fulgent Genetics, SCV002809731.1

#	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

From Baylor Genetics, SCV004198492.2

#	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

Last Updated: Oct 8, 2024

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