ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.513+2T>G
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
-
NM_170707.4(LMNA):c.513+2T>G
Variation ID: 518520 Accession: VCV000518520.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q22 1: 156130775 (GRCh38) [ NCBI UCSC ] 1: 156100566 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 14, 2018 May 1, 2024 Jun 23, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- -
- Canonical SPDI
- NC_000001.11:156130774:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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. |
|||
LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1818 | 2095 | |
LOC126805877 | - | - | - | GRCh38 | - | 156 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 21, 2022 | RCV000618096.4 | |
Uncertain significance (1) |
no assertion criteria provided
|
Sep 18, 2017 | RCV000786357.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 23, 2023 | RCV003581698.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jul 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000735383.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.513+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 2 in the LMNA gene. This nucleotide position is … (more)
The c.513+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 2 in the LMNA gene. This nucleotide position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)
|
|
Likely pathogenic
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV004280850.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 2 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 2 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: 23360689). ClinVar contains an entry for this variant (Variation ID: 518520). 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)
|
|
Uncertain significance
(Sep 18, 2017)
|
no assertion criteria provided
Method: provider interpretation
|
not provided
Affected status: unknown
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925148.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
c.513+2T>G in intron 3 (2 nucleotides after coding exon 2) of the LMNA gene (NM_170707.2; chr1-156100566-T-G) SCICD Classification: likely pathogenic, due to likely loss of … (more)
c.513+2T>G in intron 3 (2 nucleotides after coding exon 2) of the LMNA gene (NM_170707.2; chr1-156100566-T-G) SCICD Classification: likely pathogenic, due to likely loss of function and absence in general population databases. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"), if we are able to get one more affected family member with this variant (if it segregates in this patient). Gene-level evidence: Pathogenic variants in LMNA cause clinically variable diseases, called the laminopathies. These include dilated cardiomyopathy (DCM), which is typically accompanied by conduction system disease and/or arrhythmias. Sudden cardiac death can occur before the onset of LV dilation, warranting early consideration of an ICD. Other laminopathies include Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome and lipodystrophies, among others. Region-level evidence: This variant is located within a region of LMNA in which the amount of variation in cases is significantly higher than the amount of variation in controls (Amr et al. 2016). Case data (not including our patient): none · ClinVar: not present. However, all splice variants in LMNA submitted to ClinVar by clinical labs are classified as either pathogenic or likely pathogenic. · Cases in the literature: none reported Segregation data: none reported. However, this variant segregates with cardiomyopathy and conduction system disease in 2 members of one family (this family). Functional data: none reported. Impact on splicing not corroborated with functional studies. Splice site data: Per the test report, "usingthe BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native canonical splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterios in nature." This variant replaces a nucleotide at the position of a canonical splice site (+2). Conservation data: The thymine at position 513+2 is completely conserved across species. +2 is a canonical splice site. Nearby pathogenic variants at this codon or neighboring codons: Other variants in this splicing region are present in ClinVar and other canonical splice site variants are called likely pathogenic or pathogenic: c.513+1G>A, c.513+1G>C, c.513+45T>G) Population data: There is no variation at this position listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 33.3x whereas in exomes it is 55.8x. (less)
|
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 |
---|---|---|---|---|
Cardioembolic stroke related to limb-girdle muscular dystrophy 1B. | Chen CH | BMC research notes | 2013 | PMID: 23360689 |
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 |
Text-mined citations for rs1553264668 ...
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.