GALK1

protein-coding

galactokinase 1

Gene summary

Galactokinase is a major enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. [provided by RefSeq, Jul 2008]

Previous symbols:

GALK

MANE transcript

NM_000154.2

Inheritance

ClinVar variants

P:137U:141B:222

Top phenotype

Galactosemia II

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr17:75,751,594-75,765,236

External References & Databases

Ensembl (ENSG00000108479)

Transcript & Mutation Effects

hg38 • Region Span ~13.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

galactokinase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009255

Submitter: G2P

galactokinase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009255

Submitter: Orphanet

galactokinase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009255

Submitter: Myriad Women's Health

galactokinase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009255

Submitter: ClinGen

The relationship between GALK1 and galactokinase deficiency was evaluated using the ClinGen Clinical Validity Framework as of July 9, 2021. Galactokinase deficiency (also known as type II galactosemia) is an autosomal recessive disorder of galactose metabolism characterized by early onset cataracts (Ramani and Arya, 2021; PMID: 32809518). Over 40 variants in GALK1 have been reported in patients with galactokinase deficiency (Timson, 2016; PMID: 26143117). The mechanism for disease is biallelic loss of function. Biallelic variants in GALK were first reported in humans with this condition by Stambolian et al in 1995 (PMID 7670469). Ten patients with 11 unique variants in GALK (including missense, nonsense, frameshift, and canonical splice site) were curated (Stambolian et al, 1995, PMID 7670469; Asada et al, 1999, PMID 10570908; Kalaydjieva et al, 1999, PMID 10521295; Kolosha et al, 2000, PMID 10790206; Park et al, 2007, PMID 17517531; Yasmeen et al, 2010, PMID 20405025). Segregation data from two families also support this gene-disease association (Yasmeen et al, 2010, PMID 20405025). Of note, one of the variants curated, c.82C>A (p.Pro28Thr), is a founder variant in the Romani population (Kalaydjieva et al, 1999, PMID 10521295; Ramani and Arya, 2021; PMID: 32809518). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of galactokinase, which catalyzes the phosphorylation of galactose to galactose-1-phosphate (Ballard, 1966, PMID 5971794; (Stambolian et al, 1995, PMID 7670469; Timson, 2016, PMID 26143117), and the features of a galactokinase null mouse model (Ai et al, 2000; PMID 10915771). In summary, GALK1 is definitively associated with autosomal recessive galactokinase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel.

galactokinase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009255

Submitter: Natera

galactokinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009255

Submitter: Labcorp Genetics (formerly Invitae)

galactokinase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009255

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Galactosemia IIAR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Individuals may manifest with early-onset cataracts, and dietary measures (galactose/lactose restricted diet) can be effective; The presence of pseudotumor cerebri has been described, and awareness may allow prompt recognition and management

Refs: 3043741; 5109408; 5034870; 74495; 490246; 7670469; 8908517; 10570908; 10521295; 10790206; 11139256; 11978884; 12705493; 15024738; 17517531; 20405025; 21290184; 22154682; 22632133

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GALK1 variants in ClinVar

6 Conditions Cataloged

Deficiency of galactokinaseTotal: 535

Inborn genetic diseasesTotal: 62

not specifiedTotal: 27

not providedTotal: 25

GALK1-related disorderTotal: 14

Junctional epidermolysis bullosa with pyloric atresiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000154.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	213 clinvar	3 clinvar	222
missense	2 clinvar	14 clinvar	134 clinvar	4 clinvar	2 clinvar	156
nonsense	8 clinvar	23 clinvar				31
start loss	2 clinvar	3 clinvar				5
frameshift	35 clinvar	34 clinvar				69
splice donor/acceptor (+/-2bp)	1 clinvar	15 clinvar	1 clinvar			17
Total	48	89	141	217	5	500

Highest pathogenic variant AF is 0.00014871861

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000154.2	RefSeq	NP_000145.1	8	MANE Select
ENST00000588479.6	Ensembl	ENSP00000465930.1	8	MANE Select
NM_001381985.1	RefSeq	NP_001368914.1	8	Standard
ENST00000225614.6	Ensembl	ENSP00000225614.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Galactose metabolism - Homo sapiens (human)
Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
Galactosemia III
Galactosemia II (GALK)
Galactose Metabolism

Biological Process

galactose metabolic process
galactose catabolic process
galactitol metabolic process
galactose catabolic process via UDP-galactose
carbohydrate phosphorylation

Molecular Function

galactokinase activity
ATP binding
galactose binding

Cellular Component

cytoplasm
cytosol
membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000588479
Coding exons: 8
Length: 14118
Individuals with no LoFs: 125692
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125710
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.593	221	247	0.894	0.0000164	2428
Missense (PolyPhen)		63	81.443	0.77354		803
Synonymous	-0.00333	110	110	1.00	0.00000726	863
Loss of Function	1.30	10	15.5	0.644	6.66e-7	183

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000064	0.000062	rare
South Asian	0.000099	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Major enzyme for galactose metabolism.;
Disease: DISEASE: Galactosemia II (GALCT2) [MIM:230200]: Autosomal recessive deficiency characterized by congenital cataracts during infancy and presenile cataracts in the adult population. The cataracts are secondary to accumulation of galactitol in the lenses. {ECO:0000269|PubMed:10521295, ECO:0000269|PubMed:10790206, ECO:0000269|PubMed:11139256, ECO:0000269|PubMed:11231902, ECO:0000269|PubMed:12694189, ECO:0000269|PubMed:15024738}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.254
RVIS EVS: -0.84
RVIS percentile EVS: 11.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.923

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium