For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in individuals and families with congenital cataracts segregating with disease (PMID: 15208569, 26694549, 19182255, 27609163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 59 of the GJA3 protein (p.Pro59Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
ClinVar Genomic variation as it relates to human health
NM_021954.4(GJA3):c.176C>T (p.Pro59Leu)
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_021954.4(GJA3):c.176C>T (p.Pro59Leu)
Variation ID: 217339 Accession: VCV000217339.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20143113 (GRCh38) [ NCBI UCSC ] 13: 20717252 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 15, 2016 Jul 23, 2024 May 9, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_021954.4:c.176C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_068773.2:p.Pro59Leu missense NC_000013.11:g.20143113G>A NC_000013.10:g.20717252G>A NG_016399.1:g.22932C>T Q9Y6H8:p.Pro59Leu - Protein change
- P59L
- Other names
- -
- Canonical SPDI
- NC_000013.11:20143112:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| GJA3 | - | - |
GRCh38 GRCh37 |
244 | 304 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
May 1, 2021 | RCV000203321.3 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 9, 2024 | RCV000546601.11 |
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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Pathogenic
(Mar 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cataract 14 multiple types
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000645310.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in individuals and families with congenital cataracts segregating with disease (PMID: 15208569, 26694549, 19182255, 27609163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 59 of the GJA3 protein (p.Pro59Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. (less)
|
|
|
Likely pathogenic
(May 01, 2021)
|
criteria provided, single submitter
Method: research
|
Developmental cataract
Affected status: yes
Allele origin:
germline
|
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania
Accession: SCV001573165.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021
Comment:
PM2, PP1_strong, PP3. Absent/near absent from population databases. Same variant previously established as pathogenic variant (report with cataract PMID: 15208569, 19182255, 21866213, 25148791, 26694549, 27609163), … (more)
PM2, PP1_strong, PP3. Absent/near absent from population databases. Same variant previously established as pathogenic variant (report with cataract PMID: 15208569, 19182255, 21866213, 25148791, 26694549, 27609163), segregation (strong) with the disease in three families with 19 meioses (this study and PMID: 15208569, 27609163). Multiple predictive tools assessing variant as damaging/pathogenic. (less)
|
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Cataract 14 multiple types
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760315.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
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Pathogenic
(May 09, 2024)
|
criteria provided, single submitter
Method: research
|
Cataract 14 multiple types
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
|
Miami Human Genetics, University Of Miami Miller School Of Medicine
Accession: SCV005043120.1
First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Sex: female
|
|
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Pathogenic
(Jan 21, 2023)
|
criteria provided, single submitter
Method: curation
|
Cataract 14 multiple types
Affected status: yes
Allele origin:
germline
|
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania
Accession: SCV005081791.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Moderate), PM1, … (more)
Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Moderate), PM1, PM2(Supporting) PP3. The cataract phenotype/s reported for this variant are: Punctate nuclear, Pulverulent, Lamellar, and Central (Nuclear). Original variant report: PMID:15208569;19182255;21866213;25148791;27609163;26694549;34169787;36161833. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 (less)
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Pathogenic
(Jan 09, 2015)
|
no assertion criteria provided
Method: research
|
Developmental cataract
Affected status: yes
Allele origin:
unknown
|
Eye Genetics Research Group, Children's Medical Research Institute
Accession: SCV000256021.1
First in ClinVar: Jan 15, 2016 Last updated: Jan 15, 2016
Comment:
Family 26
|
|
Comment:
Comment:
Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Moderate), PM1, PM2(Supporting) PP3. The cataract phenotype/s reported for this variant are: Punctate nuclear, Pulverulent, Lamellar, and Central (Nuclear). Original variant report: PMID:15208569;19182255;21866213;25148791;27609163;26694549;34169787;36161833. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320
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. |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in individuals and families with congenital cataracts segregating with disease (PMID: 15208569, 26694549, 19182255, 27609163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 59 of the GJA3 protein (p.Pro59Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
Comment:
Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Moderate), PM1, PM2(Supporting) PP3. The cataract phenotype/s reported for this variant are: Punctate nuclear, Pulverulent, Lamellar, and Central (Nuclear). Original variant report: PMID:15208569;19182255;21866213;25148791;27609163;26694549;34169787;36161833. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pathogenic genetic variants identified in Australian families with paediatric cataract. | Jones JL | BMJ open ophthalmology | 2022 | PMID: 36161833 |
| Genetic disease is a common cause of bilateral childhood cataract in Denmark. | Kessel L | Ophthalmic genetics | 2021 | PMID: 34169787 |
| Further evidence for P59L mutation in GJA3 associated with autosomal dominant congenital cataract. | Wang L | Indian journal of ophthalmology | 2016 | PMID: 27609163 |
| Sporadic and Familial Congenital Cataracts: Mutational Spectrum and New Diagnoses Using Next-Generation Sequencing. | Ma AS | Human mutation | 2016 | PMID: 26694549 |
| Personalized diagnosis and management of congenital cataract by next-generation sequencing. | Gillespie RL | Ophthalmology | 2014 | PMID: 25148791 |
| Mutation analysis of 12 genes in Chinese families with congenital cataracts. | Sun W | Molecular vision | 2011 | PMID: 21866213 |
| Comprehensive mutational screening in a cohort of Danish families with hereditary congenital cataract. | Hansen L | Investigative ophthalmology & visual science | 2009 | PMID: 19182255 |
| A novel missense mutation in the gene for gap-junction protein alpha3 (GJA3) associated with autosomal dominant "nuclear punctate" cataracts linked to chromosome 13q. | Bennett TM | Molecular vision | 2004 | PMID: 15208569 |
Text-mined citations for rs864309691 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.