ClinVar Genomic variation as it relates to human health
NM_148960.3(CLDN19):c.59G>A (p.Gly20Asp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_148960.3(CLDN19):c.59G>A (p.Gly20Asp)
Variation ID: 1361 Accession: VCV000001361.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 42740005 (GRCh38) [ NCBI UCSC ] 1: 43205676 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 13, 2018 Oct 8, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_148960.3:c.59G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_683763.2:p.Gly20Asp missense NM_001123395.2:c.59G>A NP_001116867.1:p.Gly20Asp missense NM_001185117.2:c.59G>A NP_001172046.1:p.Gly20Asp missense NC_000001.11:g.42740005C>T NC_000001.10:g.43205676C>T NG_008993.1:g.5250G>A Q8N6F1:p.Gly20Asp - Protein change
- G20D
- Other names
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- Canonical SPDI
- NC_000001.11:42740004:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CLDN19 | - | - |
GRCh38 GRCh37 |
163 | 178 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 16, 2022 | RCV000001426.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000823362.6 | |
CLDN19-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Feb 6, 2024 | RCV003924792.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 01, 2020)
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criteria provided, single submitter
Method: research
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Renal hypomagnesemia 5 with ocular involvement
Affected status: yes
Allele origin:
inherited
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Molecular Biology Laboratory, Fundació Puigvert
Study: KidneyPanel_2020
Accession: SCV001424990.1 First in ClinVar: Jan 13, 2021 Last updated: Jan 13, 2021 |
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Pathogenic
(Apr 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Renal hypomagnesemia 5 with ocular involvement
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752656.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003915342.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
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., … (more)
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) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Renal hypomagnesemia 5 with ocular involvement
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100582.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000964216.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 01, 2006)
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no assertion criteria provided
Method: literature only
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HYPOMAGNESEMIA 5, RENAL, WITH OR WITHOUT OCULAR INVOLVEMENT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021576.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 13, 2018 |
Comment on evidence:
In 7 of 8 Spanish/Hispanic patients with a syndrome of hypomagnesemia with renal failure and ocular involvement (HOMG5; 248190), Konrad et al. (2006) identified homozygosity … (more)
In 7 of 8 Spanish/Hispanic patients with a syndrome of hypomagnesemia with renal failure and ocular involvement (HOMG5; 248190), Konrad et al. (2006) identified homozygosity for a gly20-to-asp (G20D) substitution in the first transmembrane domain of the CLDN19 protein. Expression analysis in Madin-Darby canine kidney (MDCK) cells revealed perinuclear retention of the G20D mutant, whereas wildtype claudin-19 was targeted to the cell membrane, which pointed to a trafficking defect. This trafficking defect of the mutant was explained by disturbance of the signal peptide sequence, corresponding to the first 20 amino acids of the claudin-19 protein, as predicted by in silico analysis. Godron et al. (2012) identified the c.59G-A transition (c.59G-A, NM_148960) in exon 1 of the CLDN19 gene, resulting in a G20D substitution, in 15 additional patients with HOMG5 from 14 families from southwest France or Spain. The haplotype data were consistent with a founder effect, which was previously identified by Konrad et al. (2006). In 4 affected members of 2 unrelated Brazilian families (families 1 and 2) with HOMG5, Yamaguti et al. (2017) identified compound heterozygosity for the G20D mutation and another mutation in the CLDN19 gene (see, e.g., 610036.0004). All 4 patients exhibited amelogenesis imperfecta, but 3 of them had normal vision. Yamaguti et al. (2017) also observed amelogenesis imperfecta in 2 of the French probands previously reported by Godron et al. (2012) (patients 15 and 16), who were both homozygous for the G20D mutation. Yamaguti et al. (2017) gave the nucleotide change for this mutation as c.69G-A in Figure 1E. (less)
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Pathogenic
(Mar 08, 2024)
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no assertion criteria provided
Method: clinical testing
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Renal hypomagnesemia 5 with ocular involvement
Affected status: unknown
Allele origin:
germline
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Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute
Accession: SCV004708188.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
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Pathogenic
(Feb 06, 2024)
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no assertion criteria provided
Method: clinical testing
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CLDN19-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004741667.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. | Domingo-Gallego A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2022 | PMID: 33532864 |
Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations. | Yamaguti PM | Journal of medical genetics | 2017 | PMID: 27530400 |
Haplotype analysis of CLDN19 single nucleotide polymorphisms in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. | Martin-Nuñez E | World journal of pediatrics : WJP | 2015 | PMID: 25410674 |
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: variable phenotypic expression in three affected sisters from Mexican ancestry. | Arteaga ME | Renal failure | 2015 | PMID: 25366522 |
Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. | Claverie-Martín F | PloS one | 2013 | PMID: 23301036 |
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. | Godron A | Clinical journal of the American Society of Nephrology : CJASN | 2012 | PMID: 22422540 |
Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. | Hou J | The Journal of clinical investigation | 2008 | PMID: 18188451 |
Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. | Konrad M | American journal of human genetics | 2006 | PMID: 17033971 |
Text-mined citations for rs118203979 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.