ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.1583C>A (p.Thr528Lys)
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.1583C>A (p.Thr528Lys)
Variation ID: 66849 Accession: VCV000066849.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156137207 (GRCh38) [ NCBI UCSC ] 1: 156106998 (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 Oct 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.1583C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Thr528Lys missense NM_005572.4:c.1583C>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Thr528Lys missense NM_001257374.3:c.1247C>A NP_001244303.1:p.Thr416Lys missense NM_001282624.2:c.1340C>A NP_001269553.1:p.Thr447Lys missense NM_001282625.2:c.1583C>A NP_001269554.1:p.Thr528Lys missense NM_001282626.2:c.1583C>A NP_001269555.1:p.Thr528Lys missense NM_170708.4:c.1583C>A NP_733822.1:p.Thr528Lys missense NC_000001.11:g.156137207C>A NC_000001.10:g.156106998C>A NG_008692.2:g.59635C>A LRG_254:g.59635C>A LRG_254t2:c.1583C>A P02545:p.Thr528Lys - Protein change
- T528K, T416K, T447K
- Other names
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- Canonical SPDI
- NC_000001.11:156137206:C: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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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
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 |
1839 | 2119 |
Conditions - Germline
Condition
Help
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
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2023 | RCV000057328.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 26, 2015 | RCV000201062.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2023 | RCV001045262.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000986432.9 |
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
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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
(Jun 26, 2015)
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criteria provided, single submitter
Method: clinical testing
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Benign scapuloperoneal muscular dystrophy with cardiomyopathy
(Autosomal unknown)
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000255783.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
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Likely pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hutchinson-Gilford syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135432.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Jan 04, 2023)
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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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Revvity Omics, Revvity
Accession: SCV002017166.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 03, 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: SCV000233099.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Oct 14, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001209102.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 528 of the LMNA protein (p.Thr528Lys). … (more)
This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 528 of the LMNA protein (p.Thr528Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 10739764, 20980393, 24642510, 31498906). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66849). 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. Experimental studies have shown that this missense change affects LMNA function (PMID: 21173262, 23427149). This variant disrupts the p.Thr528 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14684700, 20376791, 26165385). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: SCV000088441.1
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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Importance of early diagnosis in LMNA-related muscular dystrophy for cardiac surveillance. | Choi SA | Muscle & nerve | 2019 | PMID: 31498906 |
Cardiac effects of the c.1583 C→G LMNA mutation in two families with Emery-Dreifuss muscular dystrophy. | Zhang L | Molecular medicine reports | 2015 | PMID: 26165385 |
Congenital fiber type disproportion myopathy caused by LMNA mutations. | Kajino S | Journal of the neurological sciences | 2014 | PMID: 24642510 |
Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. | Zwerger M | Human molecular genetics | 2013 | PMID: 23427149 |
Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. | Folker ES | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21173262 |
Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients. | Mitsuhashi H | Journal of cell science | 2010 | PMID: 20980393 |
[Mutation analysis of a Chinese family with autosomal dominant Emery-Dreifuss muscular dystrophy]. | Yuan JH | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2010 | PMID: 20376791 |
Phenotypic clustering of lamin A/C mutations in neuromuscular patients. | Benedetti S | Neurology | 2007 | PMID: 17377071 |
Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes. | Vytopil M | Journal of medical genetics | 2003 | PMID: 14684700 |
Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations. | Sanna T | European heart journal | 2003 | PMID: 14659775 |
Structure of the globular tail of nuclear lamin. | Dhe-Paganon S | The Journal of biological chemistry | 2002 | PMID: 11901143 |
Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. | Ostlund C | Journal of cell science | 2001 | PMID: 11792809 |
Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. | Bonne G | Annals of neurology | 2000 | PMID: 10939567 |
Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. | Raffaele Di Barletta M | American journal of human genetics | 2000 | PMID: 10739764 |
In situ hybridization detection of HTLV-I RNA in peripheral blood mononuclear cells of TSP/HAM patients and their spouses. | Beilke MA | Journal of medical virology | 1991 | PMID: 1849984 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
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Text-mined citations for rs57629361 ...
HelpRecord last updated Oct 08, 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.