Variant summary: LMNA c.937-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site, whereas one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing, impacting approximately 55% of all transcripts, with 45% exhibiting normal splicing (e.g. Ito_2017). The variant allele was found at a frequency of 3.6e-05 in 277870 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (3.6e-05 vs 0.0001), allowing no conclusion about variant significance. c.937-7C>G has been reported in the literature in a setting of multi-gene panel testing as a VUS in one individual affected with Dilated Cardiomyopathy (e.g. Lakdawala_2012). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.937-7C>G
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.
(10)
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
Uncertain significance(6); Likely benign(1)
Uncertain significance(6); Likely benign(1)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_170707.4(LMNA):c.937-7C>G
Variation ID: 66959 Accession: VCV000066959.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q22 1: 156135894 (GRCh38) [ NCBI UCSC ] 1: 156105685 (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 Oct 20, 2013 Apr 20, 2024 Jan 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_170707.4:c.937-7C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_005572.4:c.937-7C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001257374.3:c.601-7C>G intron variant NM_001282624.2:c.694-7C>G intron variant NM_001282625.2:c.937-7C>G intron variant NM_001282626.2:c.937-7C>G intron variant NM_170708.4:c.937-7C>G intron variant NC_000001.11:g.156135894C>G NC_000001.10:g.156105685C>G NG_008692.2:g.58322C>G LRG_254:g.58322C>G LRG_254t1:c.937-7C>G LRG_254t2:c.937-7C>G - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000001.11:156135893:C: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.
-
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
- 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. |
|||
| 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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, single submitter
|
Apr 4, 2023 | RCV000057488.3 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Nov 14, 2022 | RCV000440584.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 11, 2024 | RCV000530832.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 20, 2023 | RCV000772012.6 | |
| Likely benign (1) |
criteria provided, single submitter
|
- | RCV001172638.1 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV003996513.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Nov 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766546.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: LMNA c.937-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: LMNA c.937-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site, whereas one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing, impacting approximately 55% of all transcripts, with 45% exhibiting normal splicing (e.g. Ito_2017). The variant allele was found at a frequency of 3.6e-05 in 277870 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (3.6e-05 vs 0.0001), allowing no conclusion about variant significance. c.937-7C>G has been reported in the literature in a setting of multi-gene panel testing as a VUS in one individual affected with Dilated Cardiomyopathy (e.g. Lakdawala_2012). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain Significance
(Apr 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Primary dilated cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848920.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is an intronic variant. It is not predicted to affect splicing … (more)
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is an intronic variant. It is not predicted to affect splicing but an in vitro study shows that the variant has an effect on splicing (Ito 2017). Clinvar: LB (GeneDx), VUS (Invitae). Gnomad: 0.012% (4 alleles). (less)
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001335701.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
|
|
|
Uncertain significance
(Apr 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000513494.5
First in ClinVar: Mar 08, 2017 Last updated: Apr 15, 2023 |
Comment:
Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare … (more)
Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32376792, 18796515, 28679633) (less)
|
|
|
Uncertain significance
(Apr 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000904968.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are … (more)
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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)
|
|
|
Uncertain significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000657827.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 5 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. … (more)
This sequence change falls in intron 5 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs267607681, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 22464770, 28679633, 32376792). ClinVar contains an entry for this variant (Variation ID: 66959). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain Significance
(Dec 01, 2023)
|
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: SCV004824689.1
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)
|
Comment:
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are … (more)
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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: 9
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
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: SCV002034605.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036808.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000088602.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
|
Comment:
Comment:
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is an intronic variant. It is not predicted to affect splicing but an in vitro study shows that the variant has an effect on splicing (Ito 2017). Clinvar: LB (GeneDx), VUS (Invitae). Gnomad: 0.012% (4 alleles).
Comment:
Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32376792, 18796515, 28679633)
Comment:
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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.
Comment:
This sequence change falls in intron 5 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs267607681, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 22464770, 28679633, 32376792). ClinVar contains an entry for this variant (Variation ID: 66959). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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.
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:
Variant summary: LMNA c.937-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site, whereas one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing, impacting approximately 55% of all transcripts, with 45% exhibiting normal splicing (e.g. Ito_2017). The variant allele was found at a frequency of 3.6e-05 in 277870 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (3.6e-05 vs 0.0001), allowing no conclusion about variant significance. c.937-7C>G has been reported in the literature in a setting of multi-gene panel testing as a VUS in one individual affected with Dilated Cardiomyopathy (e.g. Lakdawala_2012). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is an intronic variant. It is not predicted to affect splicing but an in vitro study shows that the variant has an effect on splicing (Ito 2017). Clinvar: LB (GeneDx), VUS (Invitae). Gnomad: 0.012% (4 alleles).
Comment:
Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32376792, 18796515, 28679633)
Comment:
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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.
Comment:
This sequence change falls in intron 5 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs267607681, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 22464770, 28679633, 32376792). ClinVar contains an entry for this variant (Variation ID: 66959). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. | Volodarsky M | Journal of medical genetics | 2021 | PMID: 32376792 |
| Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing. | Ito K | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28679633 |
| Genetic testing for dilated cardiomyopathy in clinical practice. | Lakdawala NK | Journal of cardiac failure | 2012 | PMID: 22464770 |
| Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation. | Agarwal AK | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18796515 |
Text-mined citations for rs267607681 ...
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.