This sequence change affects a donor splice site in intron 8 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 19258295, 20848652, 34240052; Invitae). ClinVar contains an entry for this variant (Variation ID: 66831). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.1488+1G>A
Germline
Classification
Help
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.
(4)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)
4
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_170707.4(LMNA):c.1488+1G>A
Variation ID: 66831 Accession: VCV000066831.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156137029 (GRCh38) [ NCBI UCSC ] 1: 156106820 (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 Sep 24, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
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- Other names
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- Canonical SPDI
- NC_000001.11:156137028: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
1845 | 2125 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
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Feb 16, 2016 | RCV000057305.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Apr 24, 2023 | RCV003298103.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 24, 2023 | RCV003581574.2 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Sep 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004292923.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 8 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 8 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 19258295, 20848652, 34240052; Invitae). ClinVar contains an entry for this variant (Variation ID: 66831). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
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Pathogenic
(Feb 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331584.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 2
Sex: mixed
|
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Uncertain significance
(Apr 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003997345.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The c.1488+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the LMNA gene. This variant has been … (more)
The c.1488+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the LMNA gene. This variant has been detected in an an individual reported to have limb girdle muscular dystrophy, partial epilepsy, and severe dilated cardiomyopathy (Tsao CY et al. J Child Neurol, 2009 Mar;24:346-8). This variant has also been detected in an individual with features of Emery-Dreifuss muscular dystrophy who required a pacemaker (Scharner J et al. Hum Mutat, 2011 Feb;32:152-67). This variant has also been detected in a cohort of patients with neuromuscular conditions; however, details were limited (Ben Yaou R et al. Brain Commun, 2021 Jul;3:fcab075). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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: SCV000088418.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
|
Comment:
Comment:
The c.1488+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the LMNA gene. This variant has been detected in an an individual reported to have limb girdle muscular dystrophy, partial epilepsy, and severe dilated cardiomyopathy (Tsao CY et al. J Child Neurol, 2009 Mar;24:346-8). This variant has also been detected in an individual with features of Emery-Dreifuss muscular dystrophy who required a pacemaker (Scharner J et al. Hum Mutat, 2011 Feb;32:152-67). This variant has also been detected in a cohort of patients with neuromuscular conditions; however, details were limited (Ben Yaou R et al. Brain Commun, 2021 Jul;3:fcab075). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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. |
Comment:
This sequence change affects a donor splice site in intron 8 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 19258295, 20848652, 34240052; Invitae). ClinVar contains an entry for this variant (Variation ID: 66831). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The c.1488+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the LMNA gene. This variant has been detected in an an individual reported to have limb girdle muscular dystrophy, partial epilepsy, and severe dilated cardiomyopathy (Tsao CY et al. J Child Neurol, 2009 Mar;24:346-8). This variant has also been detected in an individual with features of Emery-Dreifuss muscular dystrophy who required a pacemaker (Scharner J et al. Hum Mutat, 2011 Feb;32:152-67). This variant has also been detected in a cohort of patients with neuromuscular conditions; however, details were limited (Ben Yaou R et al. Brain Commun, 2021 Jul;3:fcab075). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| International retrospective natural history study of LMNA-related congenital muscular dystrophy. | Ben Yaou R | Brain communications | 2021 | PMID: 34240052 |
| Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. | Scharner J | Human mutation | 2011 | PMID: 20848652 |
| Partial epilepsy in an adolescent male with limb-girdle muscular dystrophy 1B. | Tsao CY | Journal of child neurology | 2009 | PMID: 19258295 |
| Long-term outcome and risk stratification in dilated cardiolaminopathies. | Pasotti M | Journal of the American College of Cardiology | 2008 | PMID: 18926329 |
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
Text-mined citations for rs267607640 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.