ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.73C>G (p.Arg25Gly)
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_170707.4(LMNA):c.73C>G (p.Arg25Gly)
Variation ID: 66928 Accession: VCV000066928.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156114991 (GRCh38) [ NCBI UCSC ] 1: 156084782 (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 Oct 20, 2013 Feb 14, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.73C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg25Gly missense NM_005572.4:c.73C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg25Gly missense NM_001282625.2:c.73C>G NP_001269554.1:p.Arg25Gly missense NM_001282626.2:c.73C>G NP_001269555.1:p.Arg25Gly missense NM_170708.4:c.73C>G NP_733822.1:p.Arg25Gly missense NC_000001.11:g.156114991C>G NC_000001.10:g.156084782C>G NG_008692.2:g.37419C>G LRG_254:g.37419C>G LRG_254t2:c.73C>G P02545:p.Arg25Gly - Protein change
- R25G
- Other names
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- Canonical SPDI
- NC_000001.11:156114990:C:G
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1751 | 2024 | |
LOC129931597 | - | - | - | GRCh38 | - | 99 |
Conditions - Germline
Condition
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jul 6, 2017 | RCV000057449.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV001048135.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2021 | RCV002381367.1 |
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
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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
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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
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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
(Jul 06, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000337506.4
First in ClinVar: Dec 06, 2016 Last updated: Mar 08, 2017 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Jan 10, 2017)
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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: SCV000520773.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The R25G pathogenic variant was originally reported, using alternative nomenclature, in a patient with EDMD (Vytopil et al., 2003). A subsequent study also reported the … (more)
The R25G pathogenic variant was originally reported, using alternative nomenclature, in a patient with EDMD (Vytopil et al., 2003). A subsequent study also reported the R25G variant in another individual with EDMD (Astejada et al., 2009). The R25G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and missense variants at the same position (R25C/P) and in nearby residues (S22L; T27I/S; R28W/Q) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. (less)
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Pathogenic
(Feb 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002673535.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R25G pathogenic mutation (also known as c.73C>G), located in coding exon 1 of the LMNA gene, results from a C to G substitution at … (more)
The p.R25G pathogenic mutation (also known as c.73C>G), located in coding exon 1 of the LMNA gene, results from a C to G substitution at nucleotide position 73. The arginine at codon 25 is replaced by glycine, an amino acid with dissimilar properties. This mutation (also referred to as R26G) has been detected in individuals with laminopathy-related phenotypes including limb-girdle muscular dystrophy and Emery-Dreifuss muscular dystrophy, and has shown segregation with disease in affected members of a family with neuromuscular disorders, dilated cardiomyopathy and arrhythmia (Vytopil M et al. J Med Genet, 2003 Dec;40:e132; Astejada MN et al. Acta Myol, 2007 Dec;26:159-64; Yuan WL et al. Chin Med J (Engl), 2009 Dec;122:2840-5; Cappelletti C et al. Nucleus, 2018;9:398-409). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001212125.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 25 of the LMNA protein (p.Arg25Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 25 of the LMNA protein (p.Arg25Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with limb-girdle muscular dystrophy and cardiac conduction defects (PMID: 14684700, 20092787). It has also been observed to segregate with disease in related individuals. This variant is also known as R26G. ClinVar contains an entry for this variant (Variation ID: 66928). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 31296869). For these reasons, this variant has been classified as Pathogenic. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000088563.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
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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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Cardiac and Neuromuscular Features of Patients With LMNA-Related Cardiomyopathy. | Peretto G | Annals of internal medicine | 2019 | PMID: 31476771 |
Lamin A molecular compression and sliding as mechanisms behind nucleoskeleton elasticity. | Makarov AA | Nature communications | 2019 | PMID: 31296869 |
Up-regulation of Toll-like receptors 7 and 9 and its potential implications in the pathogenic mechanisms of LMNA-related myopathies. | Cappelletti C | Nucleus (Austin, Tex.) | 2018 | PMID: 29895224 |
Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan. | Astejada MN | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2007 | PMID: 18646565 |
Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes. | Vytopil M | Journal of medical genetics | 2003 | PMID: 14684700 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
Text-mined citations for rs58327533 ...
HelpRecord last updated Feb 20, 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.