rs118203979

Positions:

chr1-42740005-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_148960.3(CLDN19):c.59G>A(p.Gly20Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,577,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CLDN19
NM_148960.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

CLDN19 (HGNC:2040): (claudin 19) 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]

CLDN19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

PP5

Variant 1-42740005-C-T is Pathogenic according to our data. Variant chr1-42740005-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42740005-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLDN19	NM_148960.3 linkuse as main transcript	c.59G>A	p.Gly20Asp	missense_variant	1/5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001185117.2 linkuse as main transcript	c.59G>A	p.Gly20Asp	missense_variant	1/3		NP_001172046.1
CLDN19	NM_001123395.2 linkuse as main transcript	c.59G>A	p.Gly20Asp	missense_variant	1/4		NP_001116867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN19	ENST00000296387.6 linkuse as main transcript	c.59G>A	p.Gly20Asp	missense_variant	1/5	2	NM_148960.3	ENSP00000296387		Q8N6F1-1
CLDN19	ENST00000372539.3 linkuse as main transcript	c.59G>A	p.Gly20Asp	missense_variant	1/4	1		ENSP00000361617	P1	Q8N6F1-2
CLDN19	ENST00000539749.5 linkuse as main transcript	c.59G>A	p.Gly20Asp	missense_variant	1/3	2		ENSP00000443229		Q8N6F1-3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000898

AC:

AN:

189278

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

101742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000426

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000376

Gnomad OTH exome

AF:

0.000401

GnomAD4 exome

AF:

0.0000224

AC:

AN:

1425394

Hom.:

Cov.:

AF XY:

0.0000241

AC XY:

AN XY:

705954

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000457

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000110

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000334

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal hypomagnesemia 5 with ocular involvement

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 16, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute	Mar 08, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 20 of the CLDN19 protein (p.Gly20Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (PMID: 17033971, 23301036, 25366522, 25410674, 27530400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1361). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLDN19 function (PMID: 17033971, 18188451). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2022	Published functional studies demonstrate a damaging effect on protein trafficking and/or assembly, impairing its function during renal tubular and retinal epithelial development (Konrad et al., 2006; Wang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18188451, Xu2017[abstract], 25366522, 30937396, 25317625, 17033971, 27530400, 22422540, 34425238, 31694170, 33532864, 25410674) -

CLDN19-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2024

The CLDN19 c.59G>A variant is predicted to result in the amino acid substitution p.Gly20Asp. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with familial hypomagnesemia, hypercalciuria, and nephrocalcinosis with ocular abnormalities (see for example, Figure 2, Konrad et al. 2006. PubMed ID: 17033971; Almeida et al. 2014. PubMed ID: 25317625; Table 1, Martin-Nuñez et al. 2014. PubMed ID: 25410674). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD. Functional studies suggest this variant impairs protein function (Figure 2, Hou et al. 2008. PubMed ID: 18188451; Figure 2, Wang et al. 2019. PubMed ID: 30937396). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.3

M;M;M

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.96

MutPred

0.70

Gain of catalytic residue at G20 (P = 0.0203);Gain of catalytic residue at G20 (P = 0.0203);Gain of catalytic residue at G20 (P = 0.0203);

MVP

0.99

MPC

1.1

ClinPred

0.82

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.97

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over