ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.116A>G (p.Asn39Ser)
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.116A>G (p.Asn39Ser)
Variation ID: 66791 Accession: VCV000066791.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156115034 (GRCh38) [ NCBI UCSC ] 1: 156084825 (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 20, 2024 Jul 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.116A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Asn39Ser missense NM_005572.4:c.116A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Asn39Ser missense NM_001282625.2:c.116A>G NP_001269554.1:p.Asn39Ser missense NM_001282626.2:c.116A>G NP_001269555.1:p.Asn39Ser missense NM_170708.4:c.116A>G NP_733822.1:p.Asn39Ser missense NC_000001.11:g.156115034A>G NC_000001.10:g.156084825A>G NG_008692.2:g.37462A>G LRG_254:g.37462A>G LRG_254t2:c.116A>G P02545:p.Asn39Ser - Protein change
- N39S
- Other names
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- Canonical SPDI
- NC_000001.11:156115033:A: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 |
1810 | 2087 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Dec 17, 2022 | RCV000057252.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 5, 2023 | RCV000557302.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 2, 2022 | RCV003458342.1 |
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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Pathogenic
(Aug 08, 2016)
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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: SCV000344645.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 17, 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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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818232.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV003802763.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
The LMNA c.116A>G (p.Asn39Ser) missense variant results in the substitution of asparagine at amino acid position 39 with serine. Across a selection of the available … (more)
The LMNA c.116A>G (p.Asn39Ser) missense variant results in the substitution of asparagine at amino acid position 39 with serine. Across a selection of the available literature, the c.116A>G variant has been identified in at least ten individuals with muscular disorders, and in five of these it was found to be de novo (PMID: 18551513; PMID: 24508248; PMID: 26098624; PMID: 33250842; PMID: 32571898; PMID: 32528171; PMID: 34240052). Functional studies demonstrated that this variant causes the variant LMNA protein to aggregate (PMID: 34862408). Other pathogenic missense changes at the same codon, including p.Asn39Lys and p.Asn39Tyr, have been reported in multiple individuals with muscular disorders. This variant is located within the N-terminal Coil 1A coiled-coil domain which is a part of the larger central rod region and is thought to be involved in head to tail interactions of nuclear lamins and in facilitating the unwinding of molecules into separate strands (PMID: 30083363; PMID: 15476822). Multiple lines of in silico predictions suggest that this variant may have a deleterious effect on the gene or gene product. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.116A>G (p.Asn39Ser) variant is classified as pathogenic for LMNA-related muscular disorders. (less)
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Pathogenic
(Jul 05, 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: SCV000657792.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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) … (more)
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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 66791). This missense change has been observed in individual(s) with Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy (PMID: 17377071, 18551513, 21520333, 24508248). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 39 of the LMNA protein (p.Asn39Ser). (less)
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Pathogenic
(Apr 07, 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: SCV000577160.3
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
Comment:
The N39S pathogenic variant in the LMNA gene was first initially reported in an individual with EDMD (Benedetti et al., 2007), and subsequently reported as … (more)
The N39S pathogenic variant in the LMNA gene was first initially reported in an individual with EDMD (Benedetti et al., 2007), and subsequently reported as an apparently de novo variant in additional individuals with LMNA-related disorders (Quijano-Roy et al., 2008; Pasqualin et al., 2014). The N39S 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 conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and different missense variants at the same position (N39Y/K) have been previously reported in association with muscular dystrophy (Prigogine et al., 2010; Tan et al., 2015). Additionally, missense variants in nearby residues (L35V/P; R41C/S; A43T) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. (less)
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Pathogenic
(Mar 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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LMNA-related disease
Affected status: unknown
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807005.2
First in ClinVar: Mar 04, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS4 strong, PM2, PM5 moderated, PM6 strong, PP3 supporting
Geographic origin: Brazil
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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: SCV000088365.1
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 |
International retrospective natural history study of LMNA-related congenital muscular dystrophy. | Ben Yaou R | Brain communications | 2021 | PMID: 34240052 |
Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients. | Fan Y | Journal of medical genetics | 2021 | PMID: 32571898 |
Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. | Chakravorty S | Frontiers in neurology | 2020 | PMID: 33250842 |
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
A novel LMNA mutation identified in a Japanese patient with LMNA-associated congenital muscular dystrophy. | Ishiyama A | Human genome variation | 2018 | PMID: 30083363 |
Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy. | Tan D | PloS one | 2015 | PMID: 26098624 |
Congenital muscular dystrophy with dropped head linked to the LMNA gene in a Brazilian cohort. | Pasqualin LM | Pediatric neurology | 2014 | PMID: 24508248 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. | Scharner J | Human mutation | 2011 | PMID: 20848652 |
De novo LMNA mutations cause a new form of congenital muscular dystrophy. | Quijano-Roy S | Annals of neurology | 2008 | PMID: 18551513 |
Phenotypic clustering of lamin A/C mutations in neuromuscular patients. | Benedetti S | Neurology | 2007 | PMID: 17377071 |
Crystal structure of the human lamin A coil 2B dimer: implications for the head-to-tail association of nuclear lamins. | Strelkov SV | Journal of molecular biology | 2004 | PMID: 15476822 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
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Text-mined citations for rs57983345 ...
HelpRecord last updated Apr 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.