NM_000155.4(GALT):c.776G>A (p.Arg259Gln) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 15, 2023
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:: RCV000319697.16

Allele description [Variation Report for NM_000155.4(GALT):c.776G>A (p.Arg259Gln)]

NM_000155.4(GALT):c.776G>A (p.Arg259Gln)

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.776G>A (p.Arg259Gln)

HGVS:

NC_000009.12:g.34648850G>A
NG_009029.2:g.7262G>A
NG_028966.1:g.1666G>A
NM_000155.4:c.776G>AMANE SELECT
NM_001258332.2:c.449G>A
NP_000146.2:p.Arg259Gln
NP_001245261.1:p.Arg150Gln
NP_001245261.1:p.Arg150Gln
NC_000009.11:g.34648847G>A
NM_000155.2:c.776G>A
NM_000155.3:c.776G>A
NM_001258332.1:c.449G>A
P07902:p.Arg259Gln

Protein change:

R150Q

Links:

UniProtKB: P07902#VAR_068548; dbSNP: rs886042070

NCBI 1000 Genomes Browser:

rs886042070

Molecular consequence:

NM_000155.4:c.776G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000695702	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27005423, 19224951, 27603904, 23418865, 22461411 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000800590	Counsyl	no assertion criteria provided	Uncertain significance (Mar 13, 2019)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22461411, 27005423, 19224951
SCV001218051	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 28, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8741038, 11152465, 23749220, 22461411, 28492532
SCV002516441	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002526392	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 10, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27603904, 23749220, 23418865, 22461411, 25741868
SCV004198527	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2023)	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	germline	yes	1	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase.

McCorvie TJ, Kopec J, Pey AL, Fitzpatrick F, Patel D, Chalk R, Shrestha L, Yue WW.

Hum Mol Genet. 2016 Jun 1;25(11):2234-2244. Epub 2016 Mar 22.

PubMed [citation]

PMID:: 27005423
PMCID:: PMC5081055

Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase.

Carney AE, Sanders RD, Garza KR, McGaha LA, Bean LJ, Coffee BW, Thomas JW, Cutler DJ, Kurtkaya NL, Fridovich-Keil JL.

Hum Mol Genet. 2009 May 1;18(9):1624-32. doi: 10.1093/hmg/ddp080. Epub 2009 Feb 18.

PubMed [citation]

PMID:: 19224951
PMCID:: PMC2667289

See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695702.1

#	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.776G>A (p.Arg259Gln) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121330 control chromosomes. This variant has been reported in at least two affected individuals via publications, and multiple clinical laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Functional study showed variant protein with no enzyme activity. Taken together, this variant is classified as likely pathogenic until more evidence becomes available.

#	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, SCV000800590.2

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

#	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, SCV001218051.5

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

Description

This variant disrupts the p.Arg259 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8741038, 11152465, 23749220). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GALT function (PMID: 22461411). 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: 280989). This missense change has been observed in individual(s) with galactosemia (PMID: 22461411). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 259 of the GALT protein (p.Arg259Gln). 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 Mendelics, SCV002516441.1

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

#	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 DASA, SCV002526392.1

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

Description

The c.776G>A;p.(Arg259Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 280989; PMID: 27603904; 23749220; 23418865; 22461411) - PS4. The variant is present at low allele frequencies population databases (rs886042070– gnomAD no frequency%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg259Gln) was detected in trans with a Pathogenic variant (PMID: 23749220; 23418865; 22461411) - PM3. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 189191 - c.775C>T (p.Arg259Trp)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is 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		1	not provided	not provided	not provided

From Baylor Genetics, SCV004198527.1

#	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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