NM_001008216.2(GALE):c.449C>T (p.Thr150Met) AND UDPglucose-4-epimerase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Dec 22, 2023
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:: RCV001331200.7

Allele description [Variation Report for NM_001008216.2(GALE):c.449C>T (p.Thr150Met)]

NM_001008216.2(GALE):c.449C>T (p.Thr150Met)

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.449C>T (p.Thr150Met)

Other names:

p.Thr150Met

HGVS:

NC_000001.11:g.23797774G>A
NG_007068.1:g.8031C>T
NM_000403.4:c.449C>T
NM_001008216.2:c.449C>TMANE SELECT
NM_001127621.2:c.449C>T
NP_000394.2:p.Thr150Met
NP_001008217.1:p.Thr150Met
NP_001121093.1:p.Thr150Met
NC_000001.10:g.24124264G>A
NM_000403.3:c.449C>T

Protein change:

T150M; THR150MET

Links:

OMIM: 606953.0011; dbSNP: rs765353795

NCBI 1000 Genomes Browser:

rs765353795

Molecular consequence:

NM_000403.4:c.449C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001008216.2:c.449C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127621.2:c.449C>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
SCV001523188	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 20, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001537895	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16385452, 34448047, 36056436, 36395340, 28492532
SCV002600028	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003928968	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 34448047, 18188677, 16385452, 36056436, 34159722 Citation Link

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	unknown	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

Citations

PubMed

Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis.

Marín-Quílez A, Di Buduo CA, Díaz-Ajenjo L, Abbonante V, Vuelta E, Soprano PM, Miguel-García C, Santos-Mínguez S, Serramito-Gómez I, Ruiz-Sala P, Peñarrubia MJ, Pardal E, Hernández-Rivas JM, González-Porras JR, García-Tuñón I, Benito R, Rivera J, Balduini A, Bastida JM.

Blood. 2023 Jan 26;141(4):406-421. doi: 10.1182/blood.2022016995.

PubMed [citation]

PMID:: 36395340
PMCID:: PMC10644051

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 (8)

Details of each submission

From Baylor Genetics, SCV001523188.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Invitae, SCV001537895.4

#	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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 150 of the GALE protein (p.Thr150Met). This variant is present in population databases (rs765353795, gnomAD 0.05%). This missense change has been observed in individual(s) with GALE-related conditions (PMID: 16385452, 34448047, 36056436, 36395340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1029823). 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 not expected to disrupt GALE protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GALE function (PMID: 36395340). 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 Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV002600028.1

#	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	germline	yes	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, SCV003928968.1

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

Description

Variant summary: GALE c.449C>T (p.Thr150Met) results in a non-conservative amino acid change located in the NAD(P)-binding domain (IPR016040) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALE causing UDPglucose-4-Epimerase Deficiency (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.449C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with UDPglucose-4-Epimerase Deficiency (Openo_2006, Derks_2022, Perea-Romero_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evaluations of the variant protein have shown contradictory effects of the variant on protein function: protein lysates from lymphoblastoid cell lines generated from a homozygous patient showed 30% residual activity (Openo_2006). However, in a yeast complementation assay, the variant protein could rescue galactose metabolism to levels comparable to cultures rescued with WT protein (Chhay_2008). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: May 12, 2024

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