NM_001008216.2(GALE):c.151C>T (p.Arg51Trp) AND UDPglucose-4-epimerase deficiency

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 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:: RCV001265572.12

Allele description [Variation Report for NM_001008216.2(GALE):c.151C>T (p.Arg51Trp)]

NM_001008216.2(GALE):c.151C>T (p.Arg51Trp)

Gene:

GALE:UDP-galactose-4-epimerase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.11

Genomic location:

Preferred name:

NM_001008216.2(GALE):c.151C>T (p.Arg51Trp)

HGVS:

NC_000001.11:g.23798701G>A
NG_007068.1:g.7104C>T
NM_000403.4:c.151C>T
NM_001008216.2:c.151C>TMANE SELECT
NM_001127621.2:c.151C>T
NP_000394.2:p.Arg51Trp
NP_001008217.1:p.Arg51Trp
NP_001121093.1:p.Arg51Trp
NC_000001.10:g.24125191G>A
NM_000403.3:c.151C>T
NM_001127621.2:c.151C>T

Protein change:

R51W; ARG51TRP

Links:

OMIM: 606953.0009; dbSNP: rs780517804

NCBI 1000 Genomes Browser:

rs780517804

Molecular consequence:

NM_000403.4:c.151C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001008216.2:c.151C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127621.2:c.151C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: UDPglucose-4-epimerase deficiency
Synonyms:: GALACTOSEMIA III; Galactose epimerase deficiency; UDP-Galactose-4-epimerase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009257; MedGen: C0751161; Orphanet: 352; OMIM: 230350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001443734	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001569152	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33510604, 30247636, 28492532
SCV002014562	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003924283	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 8, 2023)	germline	research	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, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

A Case of UDP-Galactose 4'-Epimerase Deficiency Associated with Dyshematopoiesis and Atrioventricular Valve Malformations: An Exceptional Clinical Phenotype Explained by Altered N-Glycosylation with Relative Preservation of the Leloir Pathway.

Febres-Aldana CA, Pelaez L, Wright MS, Maher OM, Febres-Aldana AJ, Sasaki J, Jayakar P, Jayakar A, Diaz-Barbosa M, Janvier M, Totapally B, Salyakina D, Galvez-Silva JR.

Mol Syndromol. 2020 Dec;11(5-6):320-329. doi: 10.1159/000511343. Epub 2020 Oct 29.

PubMed [citation]

PMID:: 33510604
PMCID:: PMC7802442

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 (4)

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001443734.1

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

Description

This variant has been previously reported as a homozygous change in multiple affected individuals from the same kindred with histories of thrombocytopenia, intracranial bleeding, anemia, and febrile neutropenia (PMID: 30247636). The variant segregated with disease in this kindred. Functional characterization of the variant protein demonstrated significantly lower enzymatic activity and greatly increased thermal instability (PMID: 30247636). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/245814) and thus is presumed to be rare. The c.151C>T (p.Arg51Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.151C>T (p.Arg51Trp) variant is classified as Likely 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		not provided	not provided	not provided	not provided

From Invitae, SCV001569152.4

#	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 tryptophan, which is neutral and slightly polar, at codon 51 of the GALE protein (p.Arg51Trp). This variant is present in population databases (rs780517804, gnomAD 0.02%). This missense change has been observed in individual(s) with GALE-related conditions and/or thrombocytopenia (PMID: 30247636, 33510604). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 984932). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GALE function (PMID: 30247636). 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 GeneReviews, SCV002014562.2

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

Description

Segregated with thrombocytopenia in a consanguineous family

#	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, SCV003924283.1

#	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: Aug 4, 2024

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