ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.448A>G (p.Thr150Ala)
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.
Likely pathogenic(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_170707.4(LMNA):c.448A>G (p.Thr150Ala)
Variation ID: 222692 Accession: VCV000222692.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q22 1: 156130708 (GRCh38) [ NCBI UCSC ] 1: 156100499 (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 Mar 1, 2016 May 1, 2024 Sep 22, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_170707.4:c.448A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Thr150Ala missense NM_005572.4:c.448A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Thr150Ala missense NM_001257374.3:c.112A>G NP_001244303.1:p.Thr38Ala missense NM_001282624.2:c.205A>G NP_001269553.1:p.Thr69Ala missense NM_001282625.2:c.448A>G NP_001269554.1:p.Thr150Ala missense NM_001282626.2:c.448A>G NP_001269555.1:p.Thr150Ala missense NM_170708.4:c.448A>G NP_733822.1:p.Thr150Ala missense NC_000001.11:g.156130708A>G NC_000001.10:g.156100499A>G NG_008692.2:g.53136A>G LRG_254:g.53136A>G LRG_254t2:c.448A>G - Protein change
- T150A, T38A, T69A
- Other names
- -
- Canonical SPDI
- NC_000001.11:156130707:A: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) 0.00001
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 16, 2023 | RCV000208276.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 22, 2023 | RCV000536399.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 2, 2017 | RCV000611547.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 5, 2019 | RCV002327072.2 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Dec 11, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000264007.2
First in ClinVar: Mar 01, 2016 Last updated: Mar 01, 2016 |
Number of individuals with the variant: 1
|
|
Uncertain significance
(May 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731631.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Thr150Ala variant in LMNA has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation … (more)
The p.Thr150Ala variant in LMNA has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Thr150Ala variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. This variant has been reported in ClinVar (Variation ID: 222692). Of n ote, a change that the same codon (p.Thr150Pro) has been classified as likely pa thogenic (LMM data), suggesting that changes at this position may not be tolerat ed. In summary, the clinical significance of the p.Thr150Ala variant is uncertai n. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Sep 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000657813.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 150 of the LMNA protein (p.Thr150Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 150 of the LMNA protein (p.Thr150Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 222692). 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. This variant disrupts the p.Thr150 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10908904, 20848652, 24503780). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
(May 16, 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: SCV004842856.1
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:
Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the first coil of the rod domain of the … (more)
Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the first coil of the rod domain of the LMNA protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disease in the literature. Another mutation at this position (p.Thr150Pro) has been identified in an individual with Dilated Cardiomyopathy and classified Likely Pathogenic (PMID 27532257). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Dec 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002635362.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.T150A variant (also known as c.448A>G), located in coding exon 2 of the LMNA gene, results from an A to G substitution at nucleotide … (more)
The p.T150A variant (also known as c.448A>G), located in coding exon 2 of the LMNA gene, results from an A to G substitution at nucleotide position 448. The threonine at codon 150 is replaced by alanine, an amino acid with similar properties, and is located in the central rod domain. A different variant affecting this codon (p.T150P, c.448A>C) has been reported in association with Emery-Dreifuss muscular dystrophy with cardiac arrhythmia, and in a dilated cardiomyopathy (DCM) cohort (Felice KJ et al. Neurology, 2000 Jul;55:275-80; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). An additional variant (p.T150I, c.449C>T) has also been reported in a DCM cohort (Hirtle-Lewis M et al. Clin Cardiol, 2013 Oct;36:628-33). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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 |
---|---|---|---|---|
Cardiometabolic assessment of lamin A/C gene mutation carriers: a phenotype-genotype correlation. | Kwapich M | Diabetes & metabolism | 2019 | PMID: 30287275 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
The genetics of dilated cardiomyopathy: a prioritized candidate gene study of LMNA, TNNT2, TCAP, and PLN. | Hirtle-Lewis M | Clinical cardiology | 2013 | PMID: 24037902 |
Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. | Scharner J | Human mutation | 2011 | PMID: 20848652 |
Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod domain of the lamin A/C gene. | Felice KJ | Neurology | 2000 | PMID: 10908904 |
Text-mined citations for rs58917027 ...
HelpRecord last updated May 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.