GALM

protein-coding

galactose mutarotase

Gene summary

This gene encodes an enzyme that catalyzes the epimerization of hexose sugars such as glucose and galactose. The encoded protein is expressed in the cytoplasm and has a preference for galactose. The encoded protein may be required for normal galactose metabolism by maintaining the equilibrium of alpha and beta anomers of galactose.[provided by RefSeq, Mar 2009]

MANE transcript

NM_138801.3

Inheritance

ClinVar variants

P:6U:65B:24

Top phenotype

Galactosemia IV

gnomAD constraint

pLI —, LoF o/e 0.99

Max pathogenic AF

—

Genomic locus

chr2:38,666,081-38,741,237

External References & Databases

Ensembl (ENSG00000143891)

Transcript & Mutation Effects

hg38 • Region Span ~75.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

galactosemia 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030105

Submitter: Ambry Genetics

galactosemia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030105

Submitter: Labcorp Genetics (formerly Invitae)

galactosemia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030105

Submitter: ClinGen

The gene *GALM* which codes for the enzyme galactose mutarotase has been classified as having a strong association with the disease galactosemia 4 according to the gene-disease validity curation process (Standard Operating Procedures Version 10) of the ACMG. Galactose mutarotase catalyzes the mutarotation of both galactose (beta-D-galactose to alpha-D-galactose) and glucose. Galactosemia 4 was discovered in 2018 after searching for the cause of elevated galactose discovered in newborn screens that couldn’t be explained by mutations in *GALT, GALK1, or GALE*. Galactosemia 4 manifests with similar symptoms to type II galactosemia (*GALK1* deficiency), i.e. early onset cataracts. Cataracts sometimes resolve with early intervention while other times require surgery. Other symptoms such as transient cholestasis, neonatal jaundice, and a portosystemic shunt that spontaneously regressed have been seen. Importantly, neurological complications including speech disorders, ataxia, and intellectual disability have not been observed. Also, the complication of primary ovarian insufficiency has not been reported, although little data is currently available for *GALM*-deficiency in adults. Because this disease is typically identified through neonatal screening in programs that directly measure galactose (the biochemical phenotype is elevated blood galactose and detection of galactose-1-phosphate) the infant is usually put on a galactose free diet which results in normalization of blood galactose and galactose-1-phosphate levels. For this reason, the implications of this disease (without treatment) later in life are not known. Also, newborn screening programs that measure *GALT* activity and not galactose could miss a *GALM* deficiency. Summary of Case Level Data (12 points): 8 probands were scored with 5 unique variants (two nonsense, one frameshift, and two missense variants). Summary of Experimental Evidence (0.5 points): This gene disease relationship is also supported by experimental evidence of the *GALM* enzymatic reaction sequence.

galactosemia 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030105

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Galactosemia IVAR

Manifestation: Biochemical; Ophthalmologic

Intervention: Biochemical

Rationale: Dietary management (with a galactose-free diet) has been reported as resulting in normal galactose levels; some have been reported as resuming a normal diet in childhood and maintaining normal galactose levels

Refs: 30451973; 30910422

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GALM variants in ClinVar

6 Conditions Cataloged

not providedTotal: 53

Inborn genetic diseasesTotal: 42

Galactosemia 4Total: 9

GALM-related disorderTotal: 8

not specifiedTotal: 3

SchizophreniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138801.3. 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			1 clinvar	16 clinvar	2 clinvar	19
missense			61 clinvar	5 clinvar	1 clinvar	67
nonsense	4 clinvar		1 clinvar			5
start loss						0
frameshift	1 clinvar	1 clinvar	1 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	5	1	65	21	3	95

Highest pathogenic variant AF is 0.00012269194

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138801.3	RefSeq	NP_620156.1	7	MANE Select
ENST00000272252.10	Ensembl	ENSP00000272252.5	7	MANE Select
ENST00000410063.5	Ensembl	ENSP00000386233.1	4	Standard
ENST00000410063.6	Ensembl	ENSP00000386233.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycolysis / Gluconeogenesis - Homo sapiens (human)
Galactose metabolism - Homo sapiens (human)
Glycolysis
Glycogenosis, Type VII. Tarui disease
Gluconeogenesis

Biological Process

glucose metabolic process
galactose metabolic process
galactose catabolic process via UDP-galactose

Molecular Function

aldose 1-epimerase activity
carbohydrate binding

Cellular Component

cytoplasm
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000272252
Coding exons: 7
Length: 75328
Individuals with no LoFs: 125578
Homozygous LoFs: 0
Heterozygous LoFs: 170
Defined: 125748
p: 0.000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.146	194	188	1.03	0.00000979	2201
Missense (PolyPhen)		74	82.866	0.89301		947
Synonymous	-0.826	89	79.6	1.12	0.00000442	694
Loss of Function	0.0512	16	16.2	0.986	7.73e-7	192

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00067	0.00067	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00092	0.00092	rare
Finnish	0.0029	0.0028	notable
European (Non-Finnish)	0.00053	0.00053	rare
South Asian	0.000065	0.000065	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mutarotase converts alpha-aldose to the beta-anomer. It is active on D-glucose, L-arabinose, D-xylose, D-galactose, maltose and lactose (By similarity). {ECO:0000250, ECO:0000269|PubMed:12753898, ECO:0000269|PubMed:15026423}.;

Recessive Scores

pRec: 0.189

Intolerance Scores

LoFtool: 0.826
RVIS EVS: -0.07
RVIS percentile EVS: 48.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.976

Gene Damage Prediction

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