CLDN19

protein-coding

claudin 19, the group of Claudins

Gene summary

The product of this gene belongs to the claudin family. It plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Defects in this gene are the cause of hypomagnesemia renal with ocular involvement (HOMGO). HOMGO is a progressive renal disease characterized by primary renal magnesium wasting with hypomagnesemia, hypercalciuria and nephrocalcinosis associated with severe ocular abnormalities such as bilateral chorioretinal scars, macular colobomata, significant myopia and nystagmus. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

MANE transcript

NM_148960.3

Inheritance

ClinVar variants

P:29U:67B:35

Top phenotype

Hypomagnesemia 5, renal, with or without ocular involvement

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr1:42,733,093-42,740,254

External References & Databases

Ensembl (ENSG00000164007)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal hypomagnesemia 5 with ocular involvementDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009548

Submitter: G2P

renal hypomagnesemia 5 with ocular involvementSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009548

Submitter: Labcorp Genetics (formerly Invitae)

renal hypomagnesemia 5 with ocular involvementSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009548

Submitter: Ambry Genetics

renal hypomagnesemia 5 with ocular involvementSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009548

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypomagnesemia 5, renal, with or without ocular involvementAR

Manifestation: Ophthalmologic; Renal

Intervention: Renal

Rationale: Electrolyte replacement and surveillance for sequelae such as urinary tract infections can be beneficial

Refs: 500385; 7947033; 17033971; 21030577; 21791920; 22422540; 23301036; 23538362

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLDN19 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 92

Renal hypomagnesemia 5 with ocular involvementTotal: 72

Inborn genetic diseasesTotal: 36

CLDN19-related disorderTotal: 11

not specifiedTotal: 8

NephrocalcinosisTotal: 1

Kidney stoneTotal: 1

Renal tubulopathiesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_148960.3. 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				30 clinvar		30
missense	3 clinvar	12 clinvar	64 clinvar	4 clinvar	1 clinvar	84
nonsense	3 clinvar	2 clinvar	1 clinvar			6
start loss						0
frameshift	1 clinvar	4 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	1 clinvar			5
Total	9	20	67	34	1	131

Highest pathogenic variant AF is 0.000023451801

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_148960.3	RefSeq	NP_683763.2	5	MANE Select
ENST00000296387.6	Ensembl	ENSP00000296387.1	5	MANE Select
NM_001123395.2	RefSeq	NP_001116867.1	4	Standard
NM_001185117.2	RefSeq	NP_001172046.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Tight junction - Homo sapiens (human)
Hepatitis C - Homo sapiens (human)
Leukocyte transendothelial migration - Homo sapiens (human)
EMT transition in Colorectal Cancer

Biological Process

visual perception
calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules
neuronal action potential propagation
apical junction assembly
response to stimulus

Molecular Function

structural molecule activity
identical protein binding

Cellular Component

nucleus
cytoplasm
bicellular tight junction
integral component of membrane
basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296387
Coding exons: 5
Length: 7162
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125700
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.779	112	138	0.813	0.00000866	1389
Missense (PolyPhen)		44	58.186	0.75619		590
Synonymous	1.46	49	63.8	0.768	0.00000461	497
Loss of Function	1.40	5	9.71	0.515	4.17e-7	108

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	0.0	absent
Finnish	0.000095	0.000092	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium- independent cell-adhesion activity. {ECO:0000250|UniProtKB:Q9ET38}.;
Disease: DISEASE: Hypomagnesemia 5, renal, with or without ocular involvement (HOMG5) [MIM:248190]: A progressive renal disease characterized by primary renal magnesium wasting with hypomagnesemia, hypercalciuria and nephrocalcinosis associated with severe ocular abnormalities such as bilateral chorioretinal scars, macular colobomata, significant myopia and nystagmus. The renal phenotype is virtually undistinguishable from that of patients with HOMG3. {ECO:0000269|PubMed:17033971}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.142

Intolerance Scores

LoFtool: 0.0854
RVIS EVS: 0.68
RVIS percentile EVS: 84.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.269

Gene Damage Prediction

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