Not observed at significant frequency in large population cohorts (gnomAD); 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: 28450710, 33708862, 33923544, 33078099, 32202185, 27535533)
ClinVar Genomic variation as it relates to human health
NM_001161748.2(LIM2):c.388C>T (p.Arg130Cys)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001161748.2(LIM2):c.388C>T (p.Arg130Cys)
Variation ID: 625113 Accession: VCV000625113.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.41 19: 51380577 (GRCh38) [ NCBI UCSC ] 19: 51883831 (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 Apr 8, 2019 Oct 8, 2024 Nov 27, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001161748.2:c.388C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001155220.1:p.Arg130Cys missense NM_030657.4:c.514C>T NP_085915.2:p.Arg172Cys missense NC_000019.10:g.51380577G>A NC_000019.9:g.51883831G>A NG_012924.1:g.12380C>T - Protein change
- R130C, R172C
- Other names
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LIM1, ARG130CYS (rs1568480054)
- Canonical SPDI
- NC_000019.10:51380576:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
variation affecting protein function; Variation Ontology [ VariO:0003]
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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.
- -
-
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. |
|||
| LIM2 | - | - |
GRCh38 GRCh37 |
64 | 105 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Nov 16, 2017 | RCV000766206.1 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 27, 2023 | RCV001212191.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 6, 2022 | RCV001799705.3 | |
|
LIM2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jan 17, 2024 | RCV003947967.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cataract 19 multiple types
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002517562.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
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Pathogenic
(Apr 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002043843.3
First in ClinVar: Jan 01, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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: 28450710, 33708862, 33923544, 33078099, 32202185, 27535533) (less)
|
|
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Likely pathogenic
(Nov 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cataract 19 multiple types
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238268.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cataract 19 multiple types
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001383767.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 172 of the LIM2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 172 of the LIM2 protein (p.Arg172Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 32202185, 33078099). It has also been observed to segregate with disease in related individuals. This variant is also known as c.388C>T (p.R130C). ClinVar contains an entry for this variant (Variation ID: 625113). 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. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 16, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Cataract
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Department of Ophthalmology, Fourth Military Medical University
Accession: SCV000897636.1
First in ClinVar: Apr 08, 2019 Last updated: Apr 08, 2019 |
Comment:
In this work, we identified a novel LIM2 mutation associated with autosomal dominant congenital membranous cataracts, which was known to be inherited by autosomal recessive … (more)
In this work, we identified a novel LIM2 mutation associated with autosomal dominant congenital membranous cataracts, which was known to be inherited by autosomal recessive pattern in all reported families with LIM2-mutant related cataract. Besides, morphological changes of the lens were characterized by macroscopically thin lenses, elongated axial length and microcosmically immature fiber cells which existed in the lens nucleus. Thus, we firstly suggest the impact of LIM2 during lens fiber cells differentiation, which could extend the understanding of the gene itself and give insight of the relationship between lens fiber cells differentiation and membranous cataract. All above are new finding and new concepts. (less)
Number of individuals with the variant: 8
Clinical Features:
Developmental cataract (present)
Ethnicity/Population group: Han Nationality
Geographic origin: China
|
|
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Pathogenic
(Jul 05, 2023)
|
no assertion criteria provided
Method: literature only
|
CATARACT 19, MULTIPLE TYPES, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV004009538.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment on evidence:
In affected members of a 4-generation British family and a 3-generation Czech family segregating autosomal dominant congenital cataract (CTRCT19; 615277), Berry et al. (2020) identified … (more)
In affected members of a 4-generation British family and a 3-generation Czech family segregating autosomal dominant congenital cataract (CTRCT19; 615277), Berry et al. (2020) identified heterozygosity for a c.388C-T transition in exon 4 of the LIM2 gene, resulting in an arg130-to-cys (R130C) substitution within the second extracellular loop. The mutation segregated with disease in both families. The cataract type was pulverulent in the British family and nuclear in the Czech family. In a large 4-generation Chinese family segregating autosomal dominant membranous cataract, Pei et al. (2020) identified heterozygosity for the c.388C-T transition (c.388C-T, NM_001161748.1) resulting in the R130C mutation in the LIM2 gene. Sanger sequencing confirmed the mutation, which segregated fully with disease and was not found in 100 unrelated controls or in the 1000 Genomes or ExAC databases. In 11 affected individuals from 4 Chinese families with congenital cataract of various types, Wang et al. (2021) identified heterozygosity for the recurrent R130C mutation in the LIM2 gene. The mutation segregated with disease in families 1, 2, and 4, and arose de novo in the proband in family 3. Haplotype analysis suggested that the mutation likely arose due to independent founder events in each family. In 11 patients from 2 Spanish families (17 and 18) with congenital cataract, Fernandez-Alcalde et al. (2021) identified heterozygosity for the recurrent R130C mutation in the LIM2 gene. The patients exhibited various cataract types, including lamellar, posterior polar, and nuclear. In 4 affected individuals over 3 generations of a Japanese family with congenital cataract, Berry et al. (2022) identified heterozygosity for the recurrent R130C mutation in the LIM2 gene. The proband was a 3-year-old girl with bilateral lamellar cataract; her 2-month-old brother had sutural cataract in the left eye and lamellar opacities in the right eye. (less)
|
|
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Pathogenic
(Jan 17, 2024)
|
no assertion criteria provided
Method: clinical testing
|
LIM2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004765079.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The LIM2 c.514C>T variant is predicted to result in the amino acid substitution p.Arg172Cys. This variant was reported as a recurrent variant in multiple individuals … (more)
The LIM2 c.514C>T variant is predicted to result in the amino acid substitution p.Arg172Cys. This variant was reported as a recurrent variant in multiple individuals with autosomal dominant cataract (reported as p.Arg130Cys in the literature, Berry et al 2020. PubMed ID: 32202185; Pei et al 2020. PubMed ID: 33078099; Wang et al 2021. PubMed ID: 33708862; Berry et al 2022. PubMed ID: 35736209; Fernández-Alcalde et al 2021. PubMed ID: 33923544). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 172 of the LIM2 protein (p.Arg172Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 32202185, 33078099). It has also been observed to segregate with disease in related individuals. This variant is also known as c.388C>T (p.R130C). ClinVar contains an entry for this variant (Variation ID: 625113). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
In this work, we identified a novel LIM2 mutation associated with autosomal dominant congenital membranous cataracts, which was known to be inherited by autosomal recessive pattern in all reported families with LIM2-mutant related cataract. Besides, morphological changes of the lens were characterized by macroscopically thin lenses, elongated axial length and microcosmically immature fiber cells which existed in the lens nucleus. Thus, we firstly suggest the impact of LIM2 during lens fiber cells differentiation, which could extend the understanding of the gene itself and give insight of the relationship between lens fiber cells differentiation and membranous cataract. All above are new finding and new concepts.
Comment:
The LIM2 c.514C>T variant is predicted to result in the amino acid substitution p.Arg172Cys. This variant was reported as a recurrent variant in multiple individuals with autosomal dominant cataract (reported as p.Arg130Cys in the literature, Berry et al 2020. PubMed ID: 32202185; Pei et al 2020. PubMed ID: 33078099; Wang et al 2021. PubMed ID: 33708862; Berry et al 2022. PubMed ID: 35736209; Fernández-Alcalde et al 2021. PubMed ID: 33923544). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
variation affecting protein function
|
Department of Ophthalmology, Fourth Military Medical University
Accession: SCV000897636.1
|
|
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); 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: 28450710, 33708862, 33923544, 33078099, 32202185, 27535533)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 172 of the LIM2 protein (p.Arg172Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 32202185, 33078099). It has also been observed to segregate with disease in related individuals. This variant is also known as c.388C>T (p.R130C). ClinVar contains an entry for this variant (Variation ID: 625113). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
In this work, we identified a novel LIM2 mutation associated with autosomal dominant congenital membranous cataracts, which was known to be inherited by autosomal recessive pattern in all reported families with LIM2-mutant related cataract. Besides, morphological changes of the lens were characterized by macroscopically thin lenses, elongated axial length and microcosmically immature fiber cells which existed in the lens nucleus. Thus, we firstly suggest the impact of LIM2 during lens fiber cells differentiation, which could extend the understanding of the gene itself and give insight of the relationship between lens fiber cells differentiation and membranous cataract. All above are new finding and new concepts.
Comment:
The LIM2 c.514C>T variant is predicted to result in the amino acid substitution p.Arg172Cys. This variant was reported as a recurrent variant in multiple individuals with autosomal dominant cataract (reported as p.Arg130Cys in the literature, Berry et al 2020. PubMed ID: 32202185; Pei et al 2020. PubMed ID: 33078099; Wang et al 2021. PubMed ID: 33708862; Berry et al 2022. PubMed ID: 35736209; Fernández-Alcalde et al 2021. PubMed ID: 33923544). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family. | Berry V | Ophthalmic genetics | 2022 | PMID: 35736209 |
| Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families. | Fernández-Alcalde C | Genes | 2021 | PMID: 33923544 |
| Elongated axial length and myopia-related fundus changes associated with the Arg130Cys mutation in the LIM2 gene in four Chinese families with congenital cataracts. | Wang X | Annals of translational medicine | 2021 | PMID: 33708862 |
| A novel mutation of LIM2 causes autosomal dominant membranous cataract in a Chinese family. | Pei R | International journal of ophthalmology | 2020 | PMID: 33078099 |
| A novel missense mutation in LIM2 causing isolated autosomal dominant congenital cataract. | Berry V | Ophthalmic genetics | 2020 | PMID: 32202185 |
Text-mined citations for rs1568480054 ...
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 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.