VCV000003682.16 - ClinVar

NM_001008216.2(GALE):c.280G>A (p.Val94Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001008216.2(GALE):c.280G>A (p.Val94Met)

Variation ID: 3682 Accession: VCV000003682.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.11 1: 23798188 (GRCh38) [ NCBI UCSC ] 1: 24124678 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Sep 29, 2024	Jan 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001008216.2:c.280G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001008217.1:p.Val94Met	missense
NM_000403.4:c.280G>A	NP_000394.2:p.Val94Met	missense
NM_001127621.2:c.280G>A	NP_001121093.1:p.Val94Met	missense
NC_000001.11:g.23798188C>T
NC_000001.10:g.24124678C>T
NG_007068.1:g.7617G>A
	Q14376:p.Val94Met

... more HGVS ... less HGVS

Protein change

V94M

Other names

Canonical SPDI

NC_000001.11:23798187:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs121908047 ClinGen: CA116434 UniProtKB: Q14376#VAR_010058 OMIM: 606953.0008 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GALE		-	-	GRCh38 GRCh37	366	387

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Galactosemia III, severe	Pathogenic (1)	no assertion criteria provided	Jun 8, 2001	RCV000003867.4
UDPglucose-4-epimerase deficiency	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 13, 2024	RCV000020292.12
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 19, 2023	RCV000727367.5
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jul 12, 2022	RCV002512728.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 01, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000707913.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (5) PubMed: 10086948‚ 11117433‚ 23644136‚ 23732289‚ 9973283 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALE Number of individuals with the variant: 1 Sex: mixed
Likely pathogenic (Jun 17, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	UDPglucose-4-epimerase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000485820.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 11117433‚ 11279193‚ 9973283‚ 18188677‚ 10086948
Likely pathogenic (Mar 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	UDPglucose-4-epimerase deficiency Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807220.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated, PP1 moderated, PP3 supporting, PP4 Number of individuals with the variant: 1 Clinical Features: Cardiomyopathy (present) , Secondary Caesarian section (present) , Liver failure (present) , Abnormal delivery (present) , Caesarian section (present) , Extremely elevated creatine kinase (present) … (more) Cardiomyopathy (present) , Secondary Caesarian section (present) , Liver failure (present) , Abnormal delivery (present) , Caesarian section (present) , Extremely elevated creatine kinase (present) , Hypergalactosemia (present) , Jaundice (present) , Neonatal respiratory distress (present) , Hearing abnormality (present) , Congestive heart failure (present) , Elevated circulating hepatic transaminase concentration (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Jan 13, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	UDPglucose-4-epimerase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004291760.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 9973283‚ 10086948‚ 28247339‚ 11117433‚ 16302980 Comment: This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 94 of the GALE protein (p.Val94Met). … (more) This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 94 of the GALE protein (p.Val94Met). This variant is present in population databases (rs121908047, gnomAD 0.003%). This missense change has been observed in individual(s) with epimerase deficiency galactosemia (PMID: 9973283, 10086948, 28247339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3682). 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: 9973283, 11117433, 16302980). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 19, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325205.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 9973283); In silico analysis supports that this missense variant has a … (more) Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 9973283); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23732289, 25150110, 16302980, 27604308, 18188677, 6408303, 11279193, 7305435, 10086948, 23644136, 11117433, 9973283, 36056436, 28247339) (less)
Likely pathogenic (Apr 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	UDPglucose-4-epimerase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002779406.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	UDPglucose-4-epimerase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002818575.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023	Comment: A Homozygous missense variation in exon 5 of the GALE gene that results in the amino acid substitution of Methionine for Valine at codon 94 … (more) A Homozygous missense variation in exon 5 of the GALE gene that results in the amino acid substitution of Methionine for Valine at codon 94 was detected. The observed variation lies in the BAR domain of APPL family of GALE protein and has previously been reported in patients affected with generalized epimerase deficiency galactosemia and functional evidence showed significant decrease in enzyme activity. The observed variant c.280G>A (p.Val94Met) has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.00793% in our internal database. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less) Age: 20-29 years Sex: female Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Pathogenic (Jul 12, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003565727.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 9973283‚ 10086948‚ 27604308‚ 28247339 Comment: The c.280G>A (p.V94M) alteration is located in exon 5 (coding exon 3) of the GALE gene. This alteration results from a G to A substitution … (more) The c.280G>A (p.V94M) alteration is located in exon 5 (coding exon 3) of the GALE gene. This alteration results from a G to A substitution at nucleotide position 280, causing the valine (V) at amino acid position 94 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (3/282652) total alleles studied. The highest observed frequency was <0.01% (1/30614) of South Asian alleles. This alteration has been detected in the homozygous state, or in conjunction with another GALE alteration, in multiple individuals with galactose epimerase deficiency (Reid, 2016; Dias Costa, 2017; Wohlers, 1999; Walter, 1999). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jun 08, 2001)	no assertion criteria provided Method: literature only	GALACTOSEMIA III, SEVERE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024032.3 First in ClinVar: Apr 04, 2013 Last updated: May 04, 2020	Publications: PubMed (4) PubMed: 9973283‚ 7305435‚ 6408303‚ 11279193 Comment on evidence: In what they claimed to be the first case of molecularly characterized severe galactose epimerase deficiency (GALAC3; 230350), Wohlers et al. (1999) identified a homozygous … (more) In what they claimed to be the first case of molecularly characterized severe galactose epimerase deficiency (GALAC3; 230350), Wohlers et al. (1999) identified a homozygous val94-to-met (V94M) missense mutation in the GALE gene. The patient was the product of a consanguineous marriage and had been described by Holton et al. (1981) and Henderson et al. (1983). She presented at age 5 days with symptoms of classic galactosemia (230400), including vomiting, hypotonia, jaundice, galactosuria, and hepatomegaly. Enzyme activities of galactose-1 phosphate uridylyltransferase (606999) and galactokinase (604313) were within normal limits. GALE activity, however, was deficient both in erythrocytes and in cultured skin fibroblasts. At age 19 months, the child remained hypotonic, with an enlarged spleen and developmental delay, despite a galactose-restricted diet (Henderson et al., 1983). Later in life, she was noted to have nerve deafness and moderate learning difficulties, but there was no evidence of ovarian dysfunction. The V94M protein is impaired relative to the wildtype enzyme predominantly at the level of V(max) rather than K(m). To address the molecular consequences of the mutation on the 3-dimensional architecture of the enzyme, Thoden et al. (2001) solved the structures of the V94M-substituted human epimerase complexed with NADH and UDP-glucose, UDP-galactose, UDP-GlcNAc, or UDP-GalNAc. They found that the net effect of the V94M substitution is an opening up of the ala93-to-glu96 surface loop, which allows free rotation of the sugars into nonproductive binding modes. (less)
not provided (-)	no classification provided Method: literature only	UDPglucose-4-epimerase deficiency Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040655.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 9973283‚ 28247339 Comment: Identified in homozygous state in persons with severe, generalized form of epimerase deficiency galactosemia

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 94 of the GALE protein (p.Val94Met). This variant is present in population databases (rs121908047, gnomAD 0.003%). This missense change has been observed in individual(s) with epimerase deficiency galactosemia (PMID: 9973283, 10086948, 28247339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3682). 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: 9973283, 11117433, 16302980). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 9973283); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23732289, 25150110, 16302980, 27604308, 18188677, 6408303, 11279193, 7305435, 10086948, 23644136, 11117433, 9973283, 36056436, 28247339)

Comment:

A Homozygous missense variation in exon 5 of the GALE gene that results in the amino acid substitution of Methionine for Valine at codon 94 was detected. The observed variation lies in the BAR domain of APPL family of GALE protein and has previously been reported in patients affected with generalized epimerase deficiency galactosemia and functional evidence showed significant decrease in enzyme activity. The observed variant c.280G>A (p.Val94Met) has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.00793% in our internal database. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

Comment:

The c.280G>A (p.V94M) alteration is located in exon 5 (coding exon 3) of the GALE gene. This alteration results from a G to A substitution at nucleotide position 280, causing the valine (V) at amino acid position 94 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (3/282652) total alleles studied. The highest observed frequency was <0.01% (1/30614) of South Asian alleles. This alteration has been detected in the homozygous state, or in conjunction with another GALE alteration, in multiple individuals with galactose epimerase deficiency (Reid, 2016; Dias Costa, 2017; Wohlers, 1999; Walter, 1999). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Epimerase Deficiency Galactosemia.	Adam MP	-	2021	PMID: 21290786
Galactose Epimerase Deficiency: Expanding the Phenotype.	Dias Costa F	JIMD reports	2017	PMID: 28247339
Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.	Reid ES	Brain : a journal of neurology	2016	PMID: 27604308
Comparison of dynamics of wildtype and V94M human UDP-galactose 4-epimerase-A computational perspective on severe epimerase-deficiency galactosemia.	Timson DJ	Gene	2013	PMID: 23732289
In silico prediction of the effects of mutations in the human UDP-galactose 4'-epimerase gene: towards a predictive framework for type III galactosemia.	McCorvie TJ	Gene	2013	PMID: 23644136
Analysis of UDP-galactose 4'-epimerase mutations associated with the intermediate form of type III galactosaemia.	Chhay JS	Journal of inherited metabolic disease	2008	PMID: 18188677
Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase.	Timson DJ	The FEBS journal	2005	PMID: 16302980
Molecular basis for severe epimerase deficiency galactosemia. X-ray structure of the human V94m-substituted UDP-galactose 4-epimerase.	Thoden JB	The Journal of biological chemistry	2001	PMID: 11279193
Studies of the V94M-substituted human UDPgalactose-4-epimerase enzyme associated with generalized epimerase-deficiency galactosaemia.	Wohlers TM	Journal of inherited metabolic disease	2000	PMID: 11117433
Generalised uridine diphosphate galactose-4-epimerase deficiency.	Walter JH	Archives of disease in childhood	1999	PMID: 10086948
Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.	Wohlers TM	American journal of human genetics	1999	PMID: 9973283
Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation.	Henderson MJ	Journal of inherited metabolic disease	1983	PMID: 6408303
Galactosaemia: a new severe variant due to uridine diphosphate galactose-4-epimerase deficiency.	Holton JB	Archives of disease in childhood	1981	PMID: 7305435
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALE	-	-	-	-
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Text-mined citations for rs121908047 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001008216.2(GALE):c.280G>A (p.Val94Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908047 ...