PLEKHM1

protein-coding

pleckstrin homology and RUN domain containing M1, the group of Pleckstrin homology domain containing

Gene summary

The protein encoded by this gene is essential for bone resorption, and may play a critical role in vesicular transport in the osteoclast. Mutations in this gene are associated with autosomal recessive osteopetrosis type 6 (OPTB6). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

MANE transcript

NM_014798.3

Inheritance

AR, AD

ClinVar variants

P:5U:158B:45

Top phenotype

Osteopetrosis, autosomal dominant 3; Osteopetrosis, autosomal recessive 6

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr17:45,435,900-45,490,758

External References & Databases

Ensembl (ENSG00000225190)

Transcript & Mutation Effects

hg38 • Region Span ~54.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive osteopetrosis 6SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012679

Submitter: Orphanet

osteopetrosis, autosomal dominant 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020848

Submitter: ClinGen

*PLEKHM1* is located at chromosome 17q21.31, has 12 exons, 1056 amino acids. It encodes a protein that is required in the late endosomal/lysosomal vesicles and bone resorption. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: autosomal dominant osteopetrosis 3 (MONDO:0020848). *PLEKHM1* was first reported in relation to autosomal dominant osteopetrosis 3 in 2008). Two unique variants(1 missense, 1 frameshift) reported in two publications have been included in this curation (PMID: 17997709, 27291868). An additional proband harboring a variant in exon 7 of the *PLEKHM1* gene variant has been reported, although the precise nature of this variant is concealed (PMID: 21054159). A total of 2.5 genetic evidence points was reached without experimental evidence. In summary, there is limited evidence supporting the relationship between *PLEKHM1* and AD osteopetrosis 3. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date (03/06/24) (SOP Version 10).

autosomal recessive osteopetrosis 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012679

Submitter: Ambry Genetics

osteopetrosis, autosomal dominant 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020848

Submitter: PanelApp Australia

autosomal recessive osteopetrosis 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012679

Submitter: PanelApp Australia

osteopetrosis, autosomal dominant 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020848

Submitter: Ambry Genetics

autosomal recessive osteopetrosis 6MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012679

Submitter: ClinGen

*PLEKHM1* is located at chromosome 17q21.31, has 12 exons, 1056 amino acids. It encodes a protein that is required in the late endosomal/lysosomal vesicles and bone resorption. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive osteopetrosis 6 (MIM#611497 ) and autosomal dominant osteopetrosis 3 (MIM#618107). This is a curation of autosomal recessive osteopetrosis 6 (MONDO:0012679). *PLEKHM1* was first reported in relation to autosomal recessive osteopetrosis 6 in 2007 (Van Wesenbeeck et al., 2007 PMID: 17404618). One variant (canonical splice-site) reported in one publication has been included in this curation (PMID: 17404618). An additional case harboring 2 heterozygous *PLEKHM1* mutations in exon 4 and exon 7 was published, although segregation data and the nature of the variants was not revealed (PMID: 28290981). The mechanism of pathogenicity is loss-of-function. A total of 3.0 genetic points was reached. This gene-disease relationship is also supported by biochemical, and mouse and rat models (PMID: 17404618, 27777970, 2122370). In summary, there is Moderate evidence supporting the relationship between *PLEKHM1* and autosomal recessive osteopetrosis 6. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date (03/06/24) (SOP Version 10).

osteopetrosis, autosomal dominant 3LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0020848

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Osteopetrosis, autosomal dominant 3; Osteopetrosis, autosomal recessive 6AD/AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17404618; 17997709; 27291868

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLEKHM1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 197

not providedTotal: 15

Osteopetrosis, autosomal dominant 3Total: 6

Autosomal recessive osteopetrosis 6Total: 3

Autosomal recessive osteopetrosis 1Total: 1

Disorder of boneTotal: 1

Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014798.3. 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	27 clinvar	1 clinvar	29
missense	1 clinvar		154 clinvar	17 clinvar		172
nonsense		2 clinvar				2
start loss						0
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	3	2	158	44	1	208

Highest pathogenic variant AF is 0.000001858918

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014798.3	RefSeq	NP_055613.1	11	MANE Select
ENST00000430334.8	Ensembl	ENSP00000389913.3	11	MANE Select
NM_001352825.2	RefSeq	NP_001339754.1	6	Standard
ENST00000446609.7	Ensembl	ENSP00000394344.3	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

autophagy
protein transport
lysosome localization
intracellular signal transduction
positive regulation of bone resorption

Molecular Function

metal ion binding

Cellular Component

nucleolus
lysosomal membrane
endosome membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000430334
Coding exons: 11
Length: 54850
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125748
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.18	531	613	0.866	0.0000408	6850
Missense (PolyPhen)		160	220.9	0.72431		2500
Synonymous	0.781	259	275	0.940	0.0000188	2194
Loss of Function	4.25	12	41.6	0.288	0.00000200	475

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000066	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Proposed to act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Seems to be involved in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion (PubMed:25498145). Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (By similarity). May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7 (PubMed:20943950). May have a role in sialyl-lex-mediated transduction of apoptotic signals (PubMed:12820725). Involved in bone resorption (By similarity). In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella- containing vacuole (SCV) probably in concert with the HOPS complex and Rab7 (PubMed:25500191). {ECO:0000250|UniProtKB:Q5PQS0, ECO:0000250|UniProtKB:Q7TSI1, ECO:0000269|PubMed:12820725, ECO:0000269|PubMed:20943950, ECO:0000269|PubMed:25498145, ECO:0000269|PubMed:25500191, ECO:0000305}.;
Disease: DISEASE: Osteopetrosis, autosomal recessive 6 (OPTB6) [MIM:611497]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. {ECO:0000269|PubMed:17404618}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.503
RVIS EVS: -1.53
RVIS percentile EVS: 3.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.745

Gene Damage Prediction

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