rs121908047

Variant names:

• chr1-23798188-C-T
• rs121908047
• NM_001008216.2:c.280G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001008216.2(GALE):​c.280G>A​(p.Val94Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: GALE NM_001008216.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.13
• Publications: 22 publications found

Genes affected

GALE (HGNC:4116): (UDP-galactose-4-epimerase) This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild ('peripheral' form) to severe ('generalized' form). Multiple alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GALE Gene-Disease associations (from GenCC):

• galactose epimerase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.32246 (below the threshold of 3.09). Trascript score misZ: 0.87424 (below the threshold of 3.09). GenCC associations: The gene is linked to galactose epimerase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 1-23798188-C-T is Pathogenic according to our data. Variant chr1-23798188-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALE	NM_001008216.2	c.280G>A	p.Val94Met	missense_variant	Exon 5 of 12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4	c.280G>A	p.Val94Met	missense_variant	Exon 5 of 12		NP_000394.2
GALE	NM_001127621.2	c.280G>A	p.Val94Met	missense_variant	Exon 4 of 11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5	c.280G>A	p.Val94Met	missense_variant	Exon 5 of 12	1	NM_001008216.2	ENSP00000483375.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251262 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461738 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46 AN XY: 727182

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1111982

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000276 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

UDPglucose-4-epimerase deficiency Pathogenic:4 Other:1

Jun 17, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Identified in homozygous state in persons with severe, generalized form of epimerase deficiency galactosemia -

Mar 18, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated, PP1 moderated, PP3 supporting, PP4 -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Dec 31, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2

May 01, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Inborn genetic diseases Pathogenic:1

Jul 12, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Galactosemia III, severe Pathogenic:1

Jun 08, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

UDPglucose-4-epimerase deficiency;C5935599:Thrombocytopenia 13, syndromic Pathogenic:1

Mar 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;T;.;D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;.;D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;.;.;.
PhyloP100		7.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	.;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.020	.;D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;.;D;.;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.93
MVP		0.90
MPC		0.50
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.72
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908047; hg19: chr1-24124678; COSMIC: COSV52527684; COSMIC: COSV52527684;