rs121908047

chr1-23798188-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 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:8 O:1
• Conservation: PhyloP100: 7.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001008216.2
• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 3682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALE	NM_001008216.2	c.280G>A	p.Val94Met	missense_variant	5/12	ENST00000617979.5
GALE	NM_000403.4	c.280G>A	p.Val94Met	missense_variant	5/12
GALE	NM_001127621.2	c.280G>A	p.Val94Met	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALE	ENST00000617979.5	c.280G>A	p.Val94Met	missense_variant	5/12	1	NM_001008216.2	P1

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

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251262 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135880

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000719

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000647 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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

UDPglucose-4-epimerase deficiency Pathogenic:5 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 17, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	Identified in homozygous state in persons with severe, generalized form of epimerase deficiency galactosemia -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 31, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 18, 2022	ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated, PP1 moderated, PP3 supporting, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 01, 2017

- -

Galactosemia III, severe Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 08, 2001

- -

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;.;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.73	T
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

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

Publications

LitVar

Other links and lift over

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