KL

klotho, the group of Glycoside hydrolase family 1

Basic information

Region (hg38): 13:33016423-33066143

Links

ENSG00000133116 ∙ NCBI:9365 ∙ OMIM:604824 ∙ HGNC:6344 ∙ Uniprot:Q9UEF7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• tumoral calcinosis, hyperphosphatemic, familial, 3 (Limited), mode of inheritance: AR
• tumoral calcinosis, hyperphosphatemic, familial, 3 (Limited), mode of inheritance: AR
• tumoral calcinosis, hyperphosphatemic, familial, 1 (Supportive), mode of inheritance: AR
• tumoral calcinosis, hyperphosphatemic, familial, 3 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Tumoral calcinosis, hyperphosphatemic, familial, 3	AR	Renal	Phosphate reduction (eg, with dietary means and phosphate-binding agents) can be beneficial	Dermatologic; Musculoskeletal; Renal	4538804; 3659264; 2777854; 12541190; 17710231

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KL gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KL gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	83	11	100
missense			182	5	9	196
nonsense			8			8
start loss			2			2
frameshift			6			6
inframe indel			4			4
splice donor/acceptor (+/-2bp)			1			1
splice region			4	2		6
non coding			32	21	18	71
Total	0	0	241	109	38

Variants in KL

This is a list of pathogenic ClinVar variants found in the KL region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
13-33016444-C-T		Tumoral calcinosis, hyperphosphatemic, familial, 3	Uncertain significance (Jul 05, 2022)
13-33016447-G-A		not specified	Uncertain significance (Mar 22, 2023)
13-33016447-G-T			Uncertain significance (Oct 29, 2021)
13-33016452-C-A			Uncertain significance (Aug 06, 2023)
13-33016452-C-T			Likely benign (Jan 26, 2022)
13-33016455-C-T		Tumoral calcinosis, hyperphosphatemic, familial, 3	Conflicting classifications of pathogenicity (Jan 26, 2024)
13-33016460-C-T		not specified	Uncertain significance (Oct 06, 2023)
13-33016472-G-GGCC			Uncertain significance (Jul 27, 2022)
13-33016476-G-A			Likely benign (Nov 19, 2023)
13-33016478-C-G			Uncertain significance (Nov 07, 2022)
13-33016484-CGTCGCT-C			Uncertain significance (Oct 03, 2023)
13-33016484-C-CGTCGCT			Uncertain significance (Oct 03, 2023)
13-33016498-C-G			Uncertain significance (Sep 24, 2021)
13-33016520-G-A		not specified	Uncertain significance (Oct 12, 2022)
13-33016527-C-T		Tumoral calcinosis, hyperphosphatemic, familial, 3	Benign (Jan 22, 2024)
13-33016531-C-T		Tumoral calcinosis, hyperphosphatemic, familial, 3	Benign (Jan 17, 2024)
13-33016545-G-A			Likely benign (Dec 11, 2023)
13-33016560-G-T			Uncertain significance (Oct 29, 2023)
13-33016564-T-C		not specified	Uncertain significance (Aug 11, 2022)
13-33016566-G-A			Uncertain significance (Dec 15, 2022)
13-33016577-C-T		not specified	Uncertain significance (Nov 18, 2022)
13-33016578-G-C			Likely benign (Apr 06, 2023)
13-33016580-G-A		Tumoral calcinosis, hyperphosphatemic, familial, 3	Benign (Jan 26, 2024)
13-33016583-C-G		not specified	Uncertain significance (Nov 30, 2022)
13-33016589-C-T			Uncertain significance (Mar 19, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KL	protein_coding	protein_coding	ENST00000380099	5	50076

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000224	1.00	125700	0	48	125748	0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.956	485	548	0.885	0.0000289	6602
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000436	0.000430
Ashkenazi Jewish	0.00	0.00
East Asian	0.000114	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000230	0.000229
Middle Eastern	0.000114	0.000109
South Asian	0.000262	0.000261
Other	0.000652	0.000652

dbNSFP

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.
• Pathway: 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;Disease;Signal Transduction;Signaling by FGFR;PI3K Cascade;IRS-mediated signalling;Insulin receptor signalling cascade;Signaling by Insulin receptor;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;PIP3 activates AKT signaling;Porphyrin metabolism;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;IRS-related events triggered by IGF1R;IGF1R signaling cascade;Signaling by Receptor Tyrosine Kinases;Intracellular signaling by second messengers;Phospholipase C-mediated cascade: FGFR1;Diseases of signal transduction;Downstream signaling of activated FGFR1;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);FGF signaling pathway;FGFR1c and Klotho ligand binding and activation;FGFR1 ligand binding and activation;FRS-mediated FGFR1 signaling;SHC-mediated cascade:FGFR1;PI-3K cascade:FGFR1;Negative regulation of FGFR1 signaling;Signaling by FGFR1 (Consensus)

Recessive Scores

• pRec: 0.493

Intolerance Scores

• loftool: 0.698
• rvis_EVS: 0.01
• rvis_percentile_EVS: 54.16

Haploinsufficiency Scores

• pHI: 0.256
• hipred: N
• hipred_score: 0.473
• ghis: 0.435

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.180

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kl
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; craniofacial phenotype; muscle phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype

Gene ontology

• Biological process: MAPK cascade;carbohydrate metabolic process;energy reserve metabolic process;aging;insulin receptor signaling pathway;fibroblast growth factor receptor signaling pathway;regulation of signaling receptor activity;positive regulation of bone mineralization;phosphatidylinositol-3-phosphate biosynthetic process;phosphatidylinositol phosphorylation;positive regulation of protein kinase B signaling;calcium ion homeostasis;positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway
• Cellular component: extracellular region;plasma membrane;integral component of plasma membrane;apical plasma membrane;extracellular exosome
• Molecular function: beta-glucuronidase activity;Ras guanyl-nucleotide exchange factor activity;fibroblast growth factor receptor binding;hormone activity;vitamin D binding;beta-glucosidase activity;1-phosphatidylinositol-3-kinase activity;fibroblast growth factor binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity