LCT

protein-coding

lactase, the group of Glycoside hydrolase family 1

Gene summary

The protein encoded by this gene belongs to the glycosyl hydrolase 1 family of proteins. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme is integral to the plasma membrane and has both phlorizin hydrolase activity and lactase activity. Mutations in this gene are associated with congenital lactase deficiency. Polymorphisms in this gene are associated with lactase persistence, in which intestinal lactase activity persists at childhood levels into adulthood. [provided by RefSeq, Jan 2016]

MANE transcript

NM_002299.4

Inheritance

ClinVar variants

P:56U:409B:374

Top phenotype

Lactase deficiency, congenital

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr2:135,787,850-135,837,184

External References & Databases

Ensembl (ENSG00000115850)

Transcript & Mutation Effects

hg38 • Region Span ~49.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital lactase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009115

Submitter: PanelApp Australia

congenital lactase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009115

Submitter: Ambry Genetics

congenital lactase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009115

Submitter: Orphanet

congenital lactase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009115

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Lactase deficiency, congenitalAR

Manifestation: Gastrointestinal

Intervention: Gastrointestinal

Rationale: Breast-feeding or lactose-containing formulas leads to severe osmotic diarrhea, which can be treated effectively with lactose-free diet

Comments: Upstream/noncoding variants may also result in adult-onset lactose intolerance

Refs: 5419986; 6847226; 9758622; 11788828; 16400612; 17345962; 19161632; 19432082; 22688420; 23445879

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LCT variants in ClinVar

5 Conditions Cataloged

not providedTotal: 784

Inborn genetic diseasesTotal: 190

Congenital lactase deficiencyTotal: 87

not specifiedTotal: 79

LCT-related disorderTotal: 40

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002299.4. 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	344 clinvar	2 clinvar	352
missense	1 clinvar	5 clinvar	398 clinvar	25 clinvar	3 clinvar	432
nonsense	12 clinvar	6 clinvar	1 clinvar			19
start loss						0
frameshift	19 clinvar	6 clinvar	3 clinvar			28
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	1 clinvar			8
Total	33	23	409	369	5	839

Highest pathogenic variant AF is 0.0003110335

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002299.4	RefSeq	NP_002290.2	17	MANE Select
ENST00000264162.7	Ensembl	ENSP00000264162.2	17	MANE Select
ENST00000452974.1	Ensembl	ENSP00000391231.1	6	Standard
ENST00001126018.1	Ensembl	ENSP00000795823.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Carbohydrate digestion and absorption - Homo sapiens (human)
Galactose metabolism - Homo sapiens (human)
Galactose Metabolism
Galactosemia
Lactose Degradation

Biological Process

carbohydrate metabolic process
polysaccharide digestion

Molecular Function

lactase activity
beta-glucosidase activity
glycosylceramidase activity

Cellular Component

plasma membrane
integral component of plasma membrane
membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264162
Coding exons: 17
Length: 49341
Individuals with no LoFs: 125462
Homozygous LoFs: 1
Heterozygous LoFs: 285
Defined: 125748
p: 0.00114

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.16	771	1.06e+3	0.727	0.0000644	12719
Missense (PolyPhen)		160	376.37	0.42511		4669
Synonymous	0.313	437	445	0.981	0.0000307	3800
Loss of Function	6.19	19	78.0	0.244	0.00000415	851

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00016	0.00016	rare
Finnish	0.010	0.010	notable
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00020	0.00020	rare
Other	0.00081	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: LPH splits lactose in the small intestine.;
Disease: DISEASE: Congenital lactase deficiency (COLACD) [MIM:223000]: Autosomal recessive, rare and severe gastrointestinal disorder. It is characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. An almost total lack of LCT activity is found in jejunal biopsy material of patients with congenital lactase deficiency. Opposite to congenital lactase deficiency, also known as lactose intolerance, is the most common enzyme deficiency worldwide. It is caused by developmental down- regulation of lactase activity during childhood or early adulthood. The decline of lactase activity is a normal physiological phenomenon; however, the majority of Northern Europeans have the ability to maintain lactase activity and digest lactose throughout life (lactase persistence). The down-regulation of lactase activity operates at the transcriptional level and it is associated with a noncoding variation in the MCM6 gene, located in the upstream vicinity of LCT. {ECO:0000269|PubMed:16400612}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.666

Intolerance Scores

LoFtool: 0.571
RVIS EVS: -1.34
RVIS percentile EVS: 4.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.837

Gene Damage Prediction

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