LAMP2

protein-coding

lysosomal associated membrane protein 2, the group of CD molecules|Lysosome associated membrane proteins

Gene summary

The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may play a role in tumor cell metastasis. It may also function in the protection, maintenance, and adhesion of the lysosome. Alternative splicing of this gene results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002294.3

Inheritance

ClinVar variants

P:145U:304B:177

Top phenotype

Danon disease

gnomAD constraint

pLI —, LoF o/e 0.25

Max pathogenic AF

—

Genomic locus

chrX:120,426,148-120,469,365

External References & Databases

Ensembl (ENSG00000005893)

Transcript & Mutation Effects

hg38 • Region Span ~43.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Danon diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010281

Submitter: PanelApp Australia

Danon diseaseSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010281

Submitter: Orphanet

Danon diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010281

Submitter: G2P

Danon diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010281

Submitter: ClinGen

The LAMP2 gene is associated with Danon disease, an X-linked disorder characterized by vacuolar cardiomyopathy, and to a lesser extent skeletal myopathy, cognitive defects and retinopathy (reviewed in Rowland et al., 2016 PMID: 27165304). As an X-linked disorder males are predominantly affected but heterozygous female carriers have been shown to develop cardiomyopathy, albeit with abated progression compared to affected males (Boucek et al., 2011 PMID: 21415759). The majority of mutations are LOF (frameshift and non-sense) but missense, splice site, and large copy number variants (CNVs), both duplications and deletions, have been reported, as well as de novo mutations. LAMP2 has three different splice isoforms (LAMP-2A, LAMP-2B, LAMP-2C) due to alternative splicing in exon 9 (terminal exon). The LAMP-2B isoform is the most widely implicated in Danon Disease, as it is found to be most abundantly expressed in the heart, skeletal muscle and brain (Konecki et al., 1995 PMID: 7488019), but does not negate the other isoforms as having a role in disease. LAMP2 is the lysosomal-associated membrane protein 2 and functions as a receptor to mediate lysosomal associated degradation or proteins, or autophagy (reviewed in D’Souza et al., 2014, PMID: 25228319). Multiple cases are reported in the literature but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is disrupted autophagy that results in aberrant vacuole accumulation in cells. This gene-disease association is supported by the function of the gene product, alteration in normal function in non-patient cells, and animal models. In summary, LAMP2 is definitively associated with Danon disease. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Data on the occurrence of cardiomyopathy in individuals with Danon disease was collected by the Hypertrophic Cardiomyopathy Gene Curation Committee (subgroup of the Cardiovascular Working Group). Mutation of LAMP2 results in the development of hypertrophic cardiomyopathy (in 88% of cases of Danon disease) that rapidly progresses to dilated cardiomyopathy (reviewed in Rowland et al., 2016 PMID: 27165304). The progression of cardiomyopathy is caused by aberrant accumulation of autophagic vacuoles in the heart and skeletal muscle. The progressive nature of LAMP2-associated cardiomyopathy requires heart transplantation by the third decade in order to avoid death (reviewed in D’Souza et al., 2014, PMID: 25228319).

Danon diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010281

Submitter: Labcorp Genetics (formerly Invitae)

Danon diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010281

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Danon diseaseXL

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Surveillance (eg, with EKG and electrocardiogram) and medical management can help decrease morbidity related to cardiomyopathy and arrhythmias; Heart transplant has been suggested to be the only truly effective treatment

Comments: Males typically display mental retardation and other recognizable features, but females may be affected with cardiomyopathy and arrhthymias

Refs: 6450334; 3806120; 3057987; 8504498; 7919972; 10972294; 12084876; 15253947; 15673802; 15889279; 15792868; 15907287; 17899313; 19318653; 21161685; 21816855; 22074992; 22365987; 22541782; 22750798

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LAMP2 variants in ClinVar

13 Conditions Cataloged

Danon diseaseTotal: 558

Cardiovascular phenotypeTotal: 175

not providedTotal: 158

not specifiedTotal: 109

LAMP2-related disorderTotal: 30

CardiomyopathyTotal: 24

LAMP2-related disordersTotal: 14

Hypertrophic cardiomyopathyTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002294.3. 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	22 clinvar	113 clinvar	1 clinvar	137
missense	3 clinvar		250 clinvar	58 clinvar	4 clinvar	315
nonsense	33 clinvar	7 clinvar	9 clinvar		1 clinvar	50
start loss	2 clinvar	4 clinvar				6
frameshift	55 clinvar	19 clinvar	1 clinvar			75
splice donor/acceptor (+/-2bp)	9 clinvar	12 clinvar	22 clinvar			43
Total	102	43	304	171	6	626

Highest pathogenic variant AF is 9.1760796e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002294.3	RefSeq	NP_002285.1	9	MANE Select
ENST00000200639.9	Ensembl	ENSP00000200639.4	9	MANE Select
NM_001122606.1	RefSeq	NP_001116078.1	9	Standard
NM_013995.2	RefSeq	NP_054701.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phagosome - Homo sapiens (human)
Autophagy - animal - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)
Senescence and Autophagy in Cancer

Biological Process

platelet degranulation
protein targeting
cellular response to starvation
protein import
regulation of protein stability

Molecular Function

protein binding
enzyme binding
protein domain specific binding

Cellular Component

extracellular space
lysosome
lysosomal membrane
late endosome
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000434600
Coding exons: 9
Length: 41539
Individuals with no LoFs: 125723
Homozygous LoFs: 1
Heterozygous LoFs: 4
Defined: 125728
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.840	116	144	0.803	0.00000998	2690
Missense (PolyPhen)		21	35.744	0.5875		717
Synonymous	1.06	43	52.8	0.815	0.00000356	818
Loss of Function	2.42	3	12.1	0.248	8.34e-7	231

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00018	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000024	0.000018	rare
South Asian	0.000052	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in chaperone-mediated autophagy, a process that mediates lysosomal degradation of proteins in response to various stresses and as part of the normal turnover of proteins with a long biological half-live (PubMed:8662539, PubMed:11082038, PubMed:18644871, PubMed:24880125, PubMed:27628032). Functions by binding target proteins, such as GAPDH and MLLT11, and targeting them for lysosomal degradation (PubMed:8662539, PubMed:11082038, PubMed:18644871, PubMed:24880125). Plays a role in lysosomal protein degradation in response to starvation (By similarity). Required for the fusion of autophagosomes with lysosomes during autophagy (PubMed:27628032). Cells that lack LAMP2 express normal levels of VAMP8, but fail to accumulate STX17 on autophagosomes, which is the most likely explanation for the lack of fusion between autophagosomes and lysosomes (PubMed:27628032). Required for normal degradation of the contents of autophagosomes (PubMed:27628032). Required for efficient MHCII-mediated presentation of exogenous antigens via its function in lysosomal protein degradation; antigenic peptides generated by proteases in the endosomal/lysosomal compartment are captured by nascent MHCII subunits (PubMed:20518820). Is not required for efficient MHCII-mediated presentation of endogenous antigens (PubMed:20518820). {ECO:0000250|UniProtKB:P17046, ECO:0000269|PubMed:11082038, ECO:0000269|PubMed:18644871, ECO:0000269|PubMed:20518820, ECO:0000269|PubMed:24880125, ECO:0000269|PubMed:27628032, ECO:0000269|PubMed:8662539}.;
Disease: DISEASE: Danon disease (DAND) [MIM:300257]: DAND is a lysosomal glycogen storage disease characterized by the clinical triad of cardiomyopathy, vacuolar myopathy and mental retardation. It is often associated with an accumulation of glycogen in muscle and lysosomes. {ECO:0000269|PubMed:15673802, ECO:0000269|PubMed:15907287}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.618

Intolerance Scores

RVIS EVS: 0.11
RVIS percentile EVS: 61.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.150

Gene Damage Prediction

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