KL

protein-coding

klotho, the group of Glycoside hydrolase family 1

Gene summary

This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004795.4

Inheritance

ClinVar variants

P:2U:334B:149

Top phenotype

Tumoral calcinosis, hyperphosphatemic, familial, 3

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr13:33,016,423-33,066,143

External References & Databases

Ensembl (ENSG00000133116)

Transcript & Mutation Effects

hg38 • Region Span ~49.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

tumoral calcinosis, hyperphosphatemic, familial, 3LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0060715

Submitter: Labcorp Genetics (formerly Invitae)

tumoral calcinosis, hyperphosphatemic, familial, 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008897

Submitter: Orphanet

tumoral calcinosis, hyperphosphatemic, familial, 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060715

Submitter: Ambry Genetics

tumoral calcinosis, hyperphosphatemic, familial, 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060715

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Tumoral calcinosis, hyperphosphatemic, familial, 3AR

Manifestation: Dermatologic; Musculoskeletal; Renal

Intervention: Renal

Rationale: Phosphate reduction (eg, with dietary means and phosphate-binding agents) can be beneficial

Refs: 4538804; 3659264; 2777854; 12541190; 17710231

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KL variants in ClinVar

6 Conditions Cataloged

not providedTotal: 405

not specifiedTotal: 163

Tumoral calcinosis, hyperphosphatemic, familial, 3Total: 98

KL-related disorderTotal: 19

AmenorrheaTotal: 2

Tumoral calcinosis, hyperphosphatemic, familial, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004795.4. 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			5 clinvar	126 clinvar	3 clinvar	134
missense		1 clinvar	308 clinvar	16 clinvar	4 clinvar	329
nonsense			9 clinvar			9
start loss			2 clinvar			2
frameshift		1 clinvar	7 clinvar			8
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	2	334	142	7	485

Highest pathogenic variant AF is 0.0000031319962

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004795.4	RefSeq	NP_004786.2	5	MANE Select
ENST00000380099.4	Ensembl	ENSP00000369442.3	5	MANE Select
ENST00001119480.1	Ensembl	ENSP00000789285.1	4	Standard
ENST00001131666.1	Ensembl	ENSP00000811086.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Longevity regulating pathway - Homo sapiens (human)
Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human)
Pentose and glucuronate interconversions - Homo sapiens (human)
Vitamin D Receptor Pathway
VEGFA-VEGFR2 Signaling Pathway

Biological Process

MAPK cascade
carbohydrate metabolic process
energy reserve metabolic process
aging
insulin receptor signaling pathway

Molecular Function

beta-glucuronidase activity
Ras guanyl-nucleotide exchange factor activity
fibroblast growth factor receptor binding
hormone activity
vitamin D binding

Cellular Component

extracellular region
plasma membrane
integral component of plasma membrane
apical plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380099
Coding exons: 5
Length: 50076
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.956	485	548	0.885	0.0000289	6602
Missense (PolyPhen)		164	201.6	0.81348		2441
Synonymous	1.06	208	228	0.911	0.0000131	2006
Loss of Function	3.59	13	36.4	0.357	0.00000181	396

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.000060	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00026	0.00026	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D (By similarity). Essential factor for the specific interaction between FGF23 and FGFR1 (By similarity). {ECO:0000250}.;
Disease: DISEASE: Tumoral calcinosis, hyperphosphatemic, familial, 3 (HFTC3) [MIM:617994]: A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. {ECO:0000269|PubMed:17710231}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.493

Intolerance Scores

LoFtool: 0.698
RVIS EVS: 0.01
RVIS percentile EVS: 54.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.180

Gene Damage Prediction

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