NM_000155.4(GALT):c.691C>T (p.Arg231Cys) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Aug 4, 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:: RCV000022184.19

Allele description [Variation Report for NM_000155.4(GALT):c.691C>T (p.Arg231Cys)]

NM_000155.4(GALT):c.691C>T (p.Arg231Cys)

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.691C>T (p.Arg231Cys)

Other names:

p.R231C:CGT>TGT

HGVS:

NC_000009.12:g.34648765C>T
NG_009029.2:g.7177C>T
NG_028966.1:g.1581C>T
NM_000155.4:c.691C>TMANE SELECT
NM_001258332.2:c.364C>T
NP_000146.2:p.Arg231Cys
NP_001245261.1:p.Arg122Cys
NC_000009.11:g.34648762C>T
NM_000155.2:c.691C>T
NM_000155.3:c.691C>T
NM_001258332.2:c.364C>T
P07902:p.Arg231Cys

Protein change:

R122C

Links:

UniProtKB: P07902#VAR_072797; dbSNP: rs111033749

NCBI 1000 Genomes Browser:

rs111033749

Molecular consequence:

NM_000155.4:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.364C>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
SCV000486527	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jun 21, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25814382, 25614870, 14518827, 22944367 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000695700	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 14, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27629047, 22944367, 14518827, 25614870 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000820402	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 4, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7550229, 11152465, 14518827, 22944367, 25614870, 25814382, 28492532
SCV003924296	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]

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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
not provided	germline	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

Citations

PubMed

Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia.

Alfadhel M, Benmeakel M, Hossain MA, Al Mutairi F, Al Othaim A, Alfares AA, Al Balwi M, Alzaben A, Eyaid W.

Orphanet J Rare Dis. 2016 Sep 15;11(1):126. doi: 10.1186/s13023-016-0510-3.

PubMed [citation]

PMID:: 27629047
PMCID:: PMC5024448

Molecular characterization of galactosemia (type 1) mutations in Japanese.

Ashino J, Okano Y, Suyama I, Yamazaki T, Yoshino M, Furuyama J, Lin HC, Reichardt JK, Isshiki G.

Hum Mutat. 1995;6(1):36-43.

PubMed [citation]

PMID:: 7550229

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000486527.2

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695700.1

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

Description

Variant summary: The GALT c.691C>T (p.Arg231Cys) variant involves the alteration of a conserved nucleotide and is located in the intersubunit interface of the protein (Boutron_2012). 4/4 in silico tools predict a damaging outcome for this variant. This variant has been reported multiple patients with galactosemia in homozygous or compound heterozygous state with other pathogenic variants (Alfadhel_2016, Boutron_2012, Schadewaldt_2003) and is absent in 121210 control chromosomes. A functional study showed this variant leads to loss of enzymatic activity (Coelho_2014). Another missense change (p.R231H) at this residue has also been reported in association with galactosemia (ARUP, ClinVar). 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000820402.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant disrupts the p.Arg231 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550229, 11152465, 22944367, 25614870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GALT protein (p.Arg231Cys). This variant is present in population databases (rs111033749, gnomAD 0.01%). This missense change has been observed in individual(s) with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 14518827, 22944367; Invitae). ClinVar contains an entry for this variant (Variation ID: 25246). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870, 25814382). 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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV003924296.1

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

Last Updated: Sep 29, 2024

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