ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.1634G>A (p.Arg545His)
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.
Pathogenic(1); Uncertain significance(24); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_170707.4(LMNA):c.1634G>A (p.Arg545His)
Variation ID: 163878 Accession: VCV000163878.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156137679 (GRCh38) [ NCBI UCSC ] 1: 156107470 (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 Mar 27, 2017 May 1, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.1634G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg545His missense NM_005572.4:c.1634G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg545His missense NM_001257374.3:c.1298G>A NP_001244303.1:p.Arg433His missense NM_001282624.2:c.1391G>A NP_001269553.1:p.Arg464His missense NM_001282625.2:c.1634G>A NP_001269554.1:p.Arg545His missense NM_001282626.2:c.1634G>A NP_001269555.1:p.Arg545His missense NM_170708.4:c.1608+447G>A intron variant NC_000001.11:g.156137679G>A NC_000001.10:g.156107470G>A NG_008692.2:g.60107G>A LRG_254:g.60107G>A LRG_254t1:c.1634G>A LRG_254p1:p.Arg545His LRG_254t2:c.1634G>A - Protein change
- R545H, R464H, R433H
- Other names
- -
- Canonical SPDI
- NC_000001.11:156137678:G:A
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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 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
Exome Aggregation Consortium (ExAC) 0.00019
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD), exomes 0.00023
The Genome Aggregation Database (gnomAD) 0.00025
Trans-Omics for Precision Medicine (TOPMed) 0.00029
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
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. |
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LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1816 | 2093 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Jun 12, 2018 | RCV000150955.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 22, 2016 | RCV000449630.8 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV000468904.16 | |
Uncertain significance (9) |
criteria provided, multiple submitters, no conflicts
|
Apr 26, 2023 | RCV000505801.31 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Nov 29, 2023 | RCV000621850.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 14, 2023 | RCV000771819.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 11, 2018 | RCV001101061.11 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 11, 2018 | RCV001101057.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 15, 2022 | RCV001101058.14 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 11, 2018 | RCV001101059.11 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 11, 2018 | RCV001101060.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 1, 2023 | RCV003993830.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003998208.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 1, 2016 | RCV000491650.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV003935266.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 11, 2018 | RCV001100810.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 11, 2018 | RCV001101055.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 11, 2018 | RCV001101062.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248958.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 2, 2021 | RCV001781492.8 | |
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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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Uncertain significance
(Aug 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Peripheral neuropathy
Affected status: yes
Allele origin:
maternal
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Claritas Genomics
Accession: SCV000537830.1
First in ClinVar: Mar 27, 2017 Last updated: Mar 27, 2017 |
Sex: female
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Uncertain significance
(Jan 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000338870.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Uncertain significance
(Jun 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198618.4
First in ClinVar: Jan 30, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.Arg545His variant in LMNA has been reported in at least 2 individuals with sudden death, 1 individual with partial lipodystrophy, 1 individual with lipody … (more)
The p.Arg545His variant in LMNA has been reported in at least 2 individuals with sudden death, 1 individual with partial lipodystrophy, 1 individual with lipody strophy and myopathy, 4 individuals with laminopathy-associated features, and se gregated with disease in 1 affected relative (LMM data, Houben 2013, van Rijsing en 2013, Chan 2016, Campuzano 2017, Neubauer 2017, Guillin-Amarelle 2018, Olaopa 2018). This variant has been reported in ClinVar (Variation ID: 163878) and has been identified in 0.05% (38/75898) of European chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs142191737). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that t he p.Arg545His variant may reduce sodium current (Olaopa 2018). However, these types of assays may not accurately represent biological function.Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, due to conflicting evidence and var iable phenotypes of affected individuals carrying the variant, the clinical sign ificance of the p.Arg545His variant is uncertain.ACMG/AMP criteria applied: PS3_ Moderate, PS4_Moderate. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Oct 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257350.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Oct 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Restrictive dermopathy 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257626.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Uncertain significance
(Oct 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1A
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257627.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Oct 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Emery-Dreifuss muscular dystrophy 2, autosomal dominant
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257624.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Uncertain significance
(Oct 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2B1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257629.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Uncertain significance
(Oct 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hutchinson-Gilford syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257630.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Uncertain significance
(Oct 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Mandibuloacral dysplasia with type A lipodystrophy
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257628.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Uncertain significance
(Oct 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Congenital muscular dystrophy due to LMNA mutation
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257631.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Uncertain significance
(Sep 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333645.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
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Uncertain significance
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1A
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440672.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
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Pathogenic
(Nov 02, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Microretrognathia
2-3 finger syndactyly Hypercholesterolemia Short stature Decreased body weight Microtia Round ear
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002026359.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
Comment:
_x000D_ Criteria applied: PS3, PS4, PM5_STR, PP3
|
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Uncertain significance
(Jul 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1A
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002517569.2
First in ClinVar: May 28, 2022 Last updated: Jul 23, 2022 |
|
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Uncertain significance
(Apr 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234709.6
First in ClinVar: Jul 05, 2015 Last updated: May 20, 2023 |
Comment:
Reported in the heterozygous state in individuals with dilated cardiomyopathy, unspecified arrhythmia, cathecholaminergic polymorphic ventricular tachycardia, isolated atrial fibrillation, left ventricle non-compaction, or metabolic syndrome … (more)
Reported in the heterozygous state in individuals with dilated cardiomyopathy, unspecified arrhythmia, cathecholaminergic polymorphic ventricular tachycardia, isolated atrial fibrillation, left ventricle non-compaction, or metabolic syndrome and lipodystrophy, with or without cardiomyopathy and proximal myopathy, but full familial segregation information was generally not provided (Klauke et al., 2017; van Lint et al., 2019; van Tienen et al., 2019; Chan et al., 2016; Guillin-Amarelle et al., 2018; Magno et al., 2021, Pessente et al., 2022; Lenarduzzi et al., 2023); Reported in the apparent homozygous state in two siblings with lipodystrophy with near-generalized loss of subcutaneous fat, diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, as well as intellectual disability, short stature, joint contractures, and cataracts; two heterozygous relatives were overweight and had acanthosis nigricans, but no evidence of lipodystrophy (Patni et al., 2020); Identified, both independently and/or in conjunction with additional variants, in other unrelated individuals referred for genetic testing at GeneDx, including one individual with a de novo pathogenic variant in another gene that was sufficient to explain their phenotype.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27498076, 30564623, 28663758, 26332594, 23183350, 29557732, 28255936, 27919367, 28074886, 29253866, 30847666, 31383942, 30420677, 34426522, 31857427, 33803191, 32041611, 34806324, 35205065, 33713793, 10939567, 35449878, 35846372, 35772917, 29791652, 36788754) (less)
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Uncertain significance
(May 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003816991.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
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Likely benign
(Jan 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000548853.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
|
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Uncertain significance
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
LMNA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004755390.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The LMNA c.1634G>A variant is predicted to result in the amino acid substitution p.Arg545His. This variant has been reported in individuals who had cardiac disease … (more)
The LMNA c.1634G>A variant is predicted to result in the amino acid substitution p.Arg545His. This variant has been reported in individuals who had cardiac disease (Table S1, van Rijsingen et al. 2013. PubMed ID: 23183350; Table S4, Neubauer et al. 2017. PubMed ID: 28074886; Table S5, Klauke et al. 2017. PubMed ID: 29253866; Guillín-Amarelle et al. 2018. PubMed ID: 29791652). This variant has also been reported in individuals with lipodystrophy or dyslipidemias (Chan et al. 2016. PubMed ID: 27919367; Table S4, Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.051% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/163878). Different substitutions that affect the same amino acid (p.Arg545Cys and p.Arg545Ser) have also been documented in association with Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy (Kandert et al. 2009. PubMed ID: 19589617; Zhang et al. 2020. PubMed ID: 32041989). At this time, the clinical significance of the c.1634G>A (p.Arg545His) variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV003916514.7
First in ClinVar: Apr 23, 2023 Last updated: Apr 15, 2024 |
Comment:
LMNA: PS3:Moderate
Number of individuals with the variant: 1
|
|
Uncertain significance
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal semi-dominant severe lipodystrophic laminopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812651.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in LMNA is predicted to replace arginine with histidine at codon 545, p.(Arg545His). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in LMNA is predicted to replace arginine with histidine at codon 545, p.(Arg545His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the lamin tail domain. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.05% (41/79,748 alleles) in the European (non-Finnish) population. This variant has been reported in individuals with LMNA-related disorders, including cardiomyopathy and lipodystrophy but has also been identified in unaffected individuals (PMID: 30420677, 31857427, 33803191, 35772917). The variant has been identified as homozygous in two siblings with lipodystrophy (PMID: 31857427). A homozygous knock-in mouse model of the variant demonstrated reduced voltage-gated sodium current, prolonged PR and QTc intervals, and increased sinus arrhythmias, which were absent in the heterozygous knock-in model (Wu et al. https://doi.org/10.1161/circ.142.suppl_3.12627Circulation). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.769). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3, PS3_Supporting. (less)
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Uncertain Significance
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004818816.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with histidine at codon 545 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 545 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a functional study, homozygous LMNA-R545H knock-in mice were reported to have reduced sodium current and increased sinus arrhythmias (Wu et al, 2020). A separate study correlated the presence of cytoplasmically located PML nuclear bodies with cells from patients with laminopathies (PMID: 22918509). However, clinical relevance of this observation is unknown. This variant has been observed in individuals affected with possible LMNA-related diseases (PMID: 22918509, 23183350, 27529282, 27919367, 29557732, 29791652, 30420677, 31857427, 33803191, 35449878; Wu et al, 2020). This variant has been identified in 48/193996 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 59
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Uncertain significance
(Nov 29, 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: SCV000736172.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R545H variant (also known as c.1634G>A), located in coding exon 10 of the LMNA gene, results from a G to A substitution at nucleotide … (more)
The p.R545H variant (also known as c.1634G>A), located in coding exon 10 of the LMNA gene, results from a G to A substitution at nucleotide position 1634. The arginine at codon 545 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as heterozygous and homozygous in association with different types of LMNA-related disease (van Rijsingen IA et al. Eur. J. Heart Fail., 2013 Apr;15:376-84; Chan D et al. J Clin Lipidol. 2016 Sep;10:1488-1491; Neubauer J et al. Eur. J. Hum. Genet., 2017 04;25:404-409; Guillín-Amarelle C et al. Arch Endocrinol Metab, 2018 Jun;62:376-382; Patni N et al. J Med Genet, 2020 06;57:422-426). This variant has also been detected in 125 participants from a biobank cohort; however, details were limited (Lazarte J et al. J Am Coll Cardiol. 2022 Jul;80(1):50-59). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Lipodystrophy (disease)
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422752.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 04, 2022 |
Comment:
The p.Arg545His variant in LMNA has been reported in 1 individual with lipodystrophy (PMID: 28074886), but has been identified in 0.05% (41/79748) of European (non-Finnish) … (more)
The p.Arg545His variant in LMNA has been reported in 1 individual with lipodystrophy (PMID: 28074886), but has been identified in 0.05% (41/79748) of European (non-Finnish) chromosomes and other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142191737). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 163878). In vitro functional studies provide some evidence that the p.Arg545His variant may slightly impact protein function (PMID: 22918509). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Arg545His have been reported in association with disease in the literature and the variant is located in a region of LMNA that is thought to be essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 28663758). In summary, the clinical significance of the p.Arg545His variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3_supporting, PM1_supporting, BA1 (Richards 2015). (less)
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Uncertain significance
(Feb 11, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002541099.2
First in ClinVar: Jul 09, 2022 Last updated: Jan 26, 2024 |
Comment:
PP3
Number of individuals with the variant: 5
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Uncertain significance
(Nov 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000904524.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 545 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 545 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a functional study, homozygous LMNA-R545H knock-in mice were reported to have reduced sodium current and increased sinus arrhythmias (Wu et al, 2020). A separate study correlated the presence of cytoplasmically located PML nuclear bodies with cells from patients with laminopathies (PMID: 22918509). However, clinical relevance of this observation is unknown. This variant has been observed in individuals affected with possible LMNA-related diseases (PMID: 22918509, 23183350, 27529282, 27919367, 29557732, 29791652, 30420677, 31857427, 33803191, 35449878; Wu et al, 2020). This variant has been identified in 48/193996 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924031.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932887.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954995.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely pathogenic
(May 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Dilated cardiomyopathy 1S
Affected status: yes
Allele origin:
germline
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Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen
Accession: SCV000298120.1
First in ClinVar: Jun 25, 2017 Last updated: Jun 25, 2017 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973367.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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LMNA Variants and Risk of Adult-Onset Cardiac Disease. | Lazarte J | Journal of the American College of Cardiology | 2022 | PMID: 35772917 |
Effect of Occurrence of Lamin A/C (LMNA) Genetic Variants in a Cohort of 101 Consecutive Apparent "Lone AF" Patients: Results and Insights. | Pessente GD | Frontiers in cardiovascular medicine | 2022 | PMID: 35449878 |
Partial Lipodystrophy and LMNA p.R545H Variant. | Magno S | Journal of clinical medicine | 2021 | PMID: 33803191 |
Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies. | Araújo de Melo Campos JT | Biochimica et biophysica acta. Molecular basis of disease | 2021 | PMID: 33713793 |
Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry. | Barriales-Villa R | Revista espanola de cardiologia (English ed.) | 2021 | PMID: 32616434 |
Homozygous LMNA p.R582H pathogenic variant reveals increasing effect on the severity of fat loss in lipodystrophy. | Soyaltin UE | Clinical diabetes and endocrinology | 2020 | PMID: 32685188 |
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant. | Patni N | Journal of medical genetics | 2020 | PMID: 31857427 |
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 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Assessment of fibroblast nuclear morphology aids interpretation of LMNA variants. | van Tienen FHJ | European journal of human genetics : EJHG | 2019 | PMID: 30420677 |
Inflammatory myopathy in the context of an unusual overlapping laminopathy. | Guillín-Amarelle C | Archives of endocrinology and metabolism | 2018 | PMID: 29791652 |
Lipodystrophic laminopathies: Diagnostic clues. | Guillín-Amarelle C | Nucleus (Austin, Tex.) | 2018 | PMID: 29557732 |
High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation. | Klauke B | PloS one | 2017 | PMID: 29253866 |
LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes. | Florwick A | Frontiers in genetics | 2017 | PMID: 28663758 |
Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis. | Campuzano O | Sports medicine (Auckland, N.Z.) | 2017 | PMID: 28255936 |
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. | Neubauer J | European journal of human genetics : EJHG | 2017 | PMID: 28074886 |
Familial partial lipodystrophy presenting as metabolic syndrome. | Chan D | Journal of clinical lipidology | 2016 | PMID: 27919367 |
Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features. | Maggi L | Cells | 2016 | PMID: 27529282 |
Inhibition of late sodium current attenuates ionic arrhythmia mechanism in ventricular myocytes expressing LaminA-N195K mutation. | Markandeya YS | Heart rhythm | 2016 | PMID: 27498076 |
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. | van Rijsingen IA | European journal of heart failure | 2013 | PMID: 23183350 |
Cytoplasmic localization of PML particles in laminopathies. | Houben F | Histochemistry and cell biology | 2013 | PMID: 22918509 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
https://academic.oup.com/eurheartj/article-pdf/39/suppl_1/ehy566.P5378/25577553/ehy566.p5378.pdf | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/00d36cdf-1e39-4614-b0b5-3f8eb0404207 | - | - | - | - |
https://www.mdpi.com/2035-8148/8/1/7127 | - | - | - | - |
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Text-mined citations for rs142191737 ...
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.