ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.497G>C (p.Arg166Pro)
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.497G>C (p.Arg166Pro)
Variation ID: 66901 Accession: VCV000066901.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156130757 (GRCh38) [ NCBI UCSC ] 1: 156100548 (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 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.497G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg166Pro missense NM_005572.4:c.497G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg166Pro missense NM_001257374.3:c.161G>C NP_001244303.1:p.Arg54Pro missense NM_001282624.2:c.254G>C NP_001269553.1:p.Arg85Pro missense NM_001282625.2:c.497G>C NP_001269554.1:p.Arg166Pro missense NM_001282626.2:c.497G>C NP_001269555.1:p.Arg166Pro missense NM_170708.4:c.497G>C NP_733822.1:p.Arg166Pro missense NC_000001.11:g.156130757G>C NC_000001.10:g.156100548G>C NG_008692.2:g.53185G>C LRG_254:g.53185G>C LRG_254t2:c.497G>C P02545:p.Arg166Pro - Protein change
- R166P, R85P, R54P
- Other names
- p.R166P:CGG>CCG
- Canonical SPDI
- NC_000001.11:156130756:G:C
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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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0.00080 (A)
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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
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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LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1818 | 2095 | |
LOC126805877 | - | - | - | GRCh38 | - | 156 |
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Dec 2, 2022 | RCV000057411.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000503619.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000556738.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2023 | RCV000620401.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV003993783.1 |
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
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
(Nov 01, 2023)
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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: SCV000736990.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R166P variant (also known as c.497G>C), located in coding exon 2 of the LMNA gene, results from a G to C substitution at nucleotide … (more)
The p.R166P variant (also known as c.497G>C), located in coding exon 2 of the LMNA gene, results from a G to C substitution at nucleotide position 497. The arginine at codon 166 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in unrelated probands with dilated cardiomyopathy (DCM), and familial cardiomyopathy with advanced atrioventricular block (Parks SB et al. Am Heart J. 2008;156(1):161-9; Saga A et al. Tohoku J Exp Med. 2009;218(4):309-16; Begay RL et al. J Am Heart Assoc. 2015 Nov;4(11)). In addition, one in vitro study using a GFP-Lamin A fusion construct suggests this variant results in altered nuclear morphology and localization (Cowan J et al. Circ Cardiovasc Genet. 2010;3(1):6-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, dilated, 1A
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595618.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Dec 02, 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: SCV000234672.15
First in ClinVar: Jul 05, 2015 Last updated: Apr 23, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in abnormal nuclear morphology and mislocalization of Lamin A (Cowan et al., 2010); This variant is associated with the following publications: (PMID: 26084686, 31383942, 31514951, 24846508, 26199943, 18585512, 19638735, 23582089, 26567375, 22337857, 32719615, 20160190, 33242466, 34045587, 34862408, 10939567) (less)
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Pathogenic
(Jan 31, 2024)
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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: SCV000657815.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 166 of the LMNA protein (p.Arg166Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 166 of the LMNA protein (p.Arg166Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial cardiomyopathy with advanced atrioventricular block and dilated cardiomyopathy (PMID: 18585512, 19638735, 26084686). ClinVar contains an entry for this variant (Variation ID: 66901). 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: 20160190). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812377.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in LMNA is predicted to replace arginine with proline at codon 166, p.(Arg166Pro). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in LMNA is predicted to replace arginine with proline at codon 166, p.(Arg166Pro). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the coil 1B domain. There is a large physicochemical difference between arginine and proline. This variant is present in a single Europrean (non-Finnish) individual from the population database gnomAD v3.1. This variant has been reported in at least four probands with a phenotype suggestive of LMNA-related cardiomyopathy which includes dilated cardiomyopathy and arrhythmia and/or conduction system disease (PMID: 18585512, 19638735, 30739589). The variant has been reported to segregate with cardiomyopathy in affected family members from one family (PMID: 33029862). Nuclear aggregation assays in cell lines showed increased aggregation indicating that this variant impacts protein function (PMID: 20160190, 34862408). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4, PS3_Moderate, PM2_Supporting, PP1, PP3. (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: SCV000088524.1
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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Most myopathic lamin variants aggregate: a functional genomics approach for assessing variants of uncertain significance. | Anderson CL | NPJ genomic medicine | 2021 | PMID: 34862408 |
Impact of variant reclassification in the clinical setting of cardiovascular genetics. | VanDyke RE | Journal of genetic counseling | 2021 | PMID: 33029862 |
A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes. | Park J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31383942 |
Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. | Gigli M | Journal of the American College of Cardiology | 2019 | PMID: 31514951 |
Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy. | Cheedipudi SM | Circulation research | 2019 | PMID: 30739589 |
Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. | Akinrinade O | European heart journal | 2015 | PMID: 26084686 |
Morphological analysis of 13 LMNA variants identified in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. | Cowan J | Circulation. Cardiovascular genetics | 2010 | PMID: 20160190 |
Lamin A/C gene mutations in familial cardiomyopathy with advanced atrioventricular block and arrhythmia. | Saga A | The Tohoku journal of experimental medicine | 2009 | PMID: 19638735 |
Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. | Parks SB | American heart journal | 2008 | PMID: 18585512 |
Text-mined citations for rs267607570 ...
HelpRecord last updated May 01, 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.