NM_000155.4(GALT):c.772C>T (p.Arg258Cys) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jan 8, 2024
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:: RCV000078235.26

Allele description [Variation Report for NM_000155.4(GALT):c.772C>T (p.Arg258Cys)]

NM_000155.4(GALT):c.772C>T (p.Arg258Cys)

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.772C>T (p.Arg258Cys)

HGVS:

NC_000009.12:g.34648846C>T
NG_009029.2:g.7258C>T
NG_028966.1:g.1662C>T
NM_000155.4:c.772C>TMANE SELECT
NM_001258332.2:c.445C>T
NP_000146.2:p.Arg258Cys
NP_000146.2:p.Arg258Cys
NP_001245261.1:p.Arg149Cys
NP_001245261.1:p.Arg149Cys
NC_000009.11:g.34648843C>T
NM_000155.2:c.772C>T
NM_000155.3:c.772C>T
NM_001258332.1:c.445C>T
P07902:p.Arg258Cys

Protein change:

R149C

Links:

UniProtKB: P07902#VAR_002605; dbSNP: rs368166217

NCBI 1000 Genomes Browser:

rs368166217

Molecular consequence:

NM_000155.4:c.772C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.445C>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
SCV000800530	Counsyl	no assertion criteria provided	Likely pathogenic (Mar 13, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17876724, 23690308, 30808388, 10960497, 15633893
SCV000931179	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10960497, 30718057, 28492532
SCV001469241	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Likely pathogenic (Oct 11, 2020)	germline	clinical testing
SCV003808590	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198490	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 30, 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	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene.

Calderon FR, Nelson L, Dobrowolski P, Sinitsyna I, Phansalkar A, Longo N, Pasquali M, Mao R.

J Inherit Metab Dis. 2007 Oct;30(5):818. Epub 2007 Sep 17.

PubMed [citation]

PMID:: 17876724

Modifiers of ovarian function in girls and women with classic galactosemia.

Spencer JB, Badik JR, Ryan EL, Gleason TJ, Broadaway KA, Epstein MP, Fridovich-Keil JL.

J Clin Endocrinol Metab. 2013 Jul;98(7):E1257-65. doi: 10.1210/jc.2013-1374. Epub 2013 May 20.

PubMed [citation]

PMID:: 23690308
PMCID:: PMC3701263

See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000800530.2

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

#	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 Invitae, SCV000931179.4

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein (p.Arg258Cys). This variant is present in population databases (rs368166217, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 10960497, 30718057; Invitae). 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: 92522). 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 95%. 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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001469241.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003808590.2

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

From Baylor Genetics, SCV004198490.1

#	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: Jun 9, 2024

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Relating variation to medicine