ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)
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.
Pathogenic(5); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)
Variation ID: 66762 Accession: VCV000066762.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156136009 (GRCh38) [ NCBI UCSC ] 1: 156105800 (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 Apr 20, 2024 Dec 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.1045C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg349Trp missense NM_005572.4:c.1045C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg349Trp missense NM_001257374.3:c.709C>T NP_001244303.1:p.Arg237Trp missense NM_001282624.2:c.802C>T NP_001269553.1:p.Arg268Trp missense NM_001282625.2:c.1045C>T NP_001269554.1:p.Arg349Trp missense NM_001282626.2:c.1045C>T NP_001269555.1:p.Arg349Trp missense NM_170708.4:c.1045C>T NP_733822.1:p.Arg349Trp missense NC_000001.11:g.156136009C>T NC_000001.10:g.156105800C>T NG_008692.2:g.58437C>T LRG_254:g.58437C>T LRG_254t1:c.1045C>T LRG_254p1:p.Arg349Trp LRG_254t2:c.1045C>T - Protein change
- R349W, R237W, R268W
- Other names
- p.R349W:CGG>TGG
- Canonical SPDI
- NC_000001.11:156136008:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
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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
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 |
1820 | 2097 |
Conditions - Germline
Condition
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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
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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. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 24, 2020 | RCV000057218.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 17, 2015 | RCV000500548.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV000653911.11 | |
not provided (1) |
no classification provided
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- | RCV000845011.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2017 | RCV000754811.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 2, 2021 | RCV002504959.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 26, 2023 | RCV003996495.2 |
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
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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
(Apr 11, 2013)
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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: SCV000234693.9
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
p.Arg349Trp (CGG>TGG): c.1045 C>T in exon 6 of the LMNA gene (NM_170707.2). The Arg349Trp mutation in the LMNA gene has been reported in one individual … (more)
p.Arg349Trp (CGG>TGG): c.1045 C>T in exon 6 of the LMNA gene (NM_170707.2). The Arg349Trp mutation in the LMNA gene has been reported in one individual with atypical partial lipodystrophy (Mory P et al., 2012). In addition, a mutation affecting this same residue, (Arg349Leu), has been reported in three individuals from one family, all of whom required cardiac transplantation at ages 18, 20, and 36 years (Hermida-Prieto M et al., 2004). Mutations in nearby residues (Glu347Lys, Ala350Pro, Gln353Lys) have been reported in association with DCM and conduction defects, further supporting the functional importance of this residue and this region of the protein. Arg349Trp was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Arg349Trp in the LMNA gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s). (less)
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Pathogenic
(Aug 17, 2015)
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criteria provided, single submitter
Method: clinical testing
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Lipodystrophy, familial partial, 2
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595602.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Likely pathogenic
(Oct 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Monogenic diabetes
Affected status: yes
Allele origin:
germline
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Translational Genomics Laboratory, University of Maryland School of Medicine
Accession: SCV000882461.1
First in ClinVar: Feb 11, 2019 Last updated: Feb 11, 2019 |
Comment:
The c.1045C>T variant in codon 349 (exon 6) of the Lamin A/C gene, LMNA, results in the substitution of Arginine to Tryptophan. Mutations in the … (more)
The c.1045C>T variant in codon 349 (exon 6) of the Lamin A/C gene, LMNA, results in the substitution of Arginine to Tryptophan. Mutations in the LMNA gene have been found to cause multiple disorders, collectively known as A-type laminopathies, that have overlapping signs and symptoms (23853504; 20074070; OMIM 150330). A-type laminopathies include familial partial lipodystrophy type 2 (also called familial partial lipodystrophy, Dunnigan type), Limb-Girdle muscular dystrophy type 1B, Emery-Dreifuss muscular dystrophy, Charcot-Marie-Tooth type 2B1 disease, Hutchinson-Gilford progeria, Heart-hand syndrome, Slovenian type, mandibuloacral dysplasia, Malouf syndrome, and familial dilated cardiomyopathy.1-3 To date, no clear genotype-phenotype correlations have been identified (23853504; 20074070). The c.1045C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the p.Arg349Trp substitution has been identified in patients with skeletal, cardiac and metabolic phenotypes (23853504; 24080738; 2270059). The c.1045C>T variant has been identified in multiple affected individuals in four generations of a family with familial partial lipodystrophy4, as well as in an 18-year old boy with atypical partial lipodystrophy as a de novo change (2270059). A different amino acid change at this same residue, p.Arg349Leu, was identified in a mother and two daughters with dilated cardiomyopathy (15219508). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, FATHMM, MetaSVM, MetalR, Provean, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PM2, PM6, PP1, PP3 (less)
Clinical Features:
Hyperglycemia (present)
Secondary finding: no
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Pathogenic
(Dec 27, 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: SCV000775801.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 349 of the LMNA protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 349 of the LMNA protein (p.Arg349Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lipodystrophy and/or renal disease or dilated cardiomyopathy (PMID: 18035086, 22700598, 23349452, 24080738, 28620495, 28641778). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66762). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg349 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15219508, 25163546, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 24, 2020)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715570.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS4, PP1_strong, PM2, PM5, PP3
Number of individuals with the variant: 2
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Familial partial lipodystrophy, Dunnigan type
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072991.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.R349W in LMNA (NM_170707.4) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported to … (more)
The missense variant p.R349W in LMNA (NM_170707.4) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported to segregate in a family affected with partial lipodystrophy and renal disease (Thong et al., 2013) and has been reported in individuals with lipodystrophy with and without renal disease or dilated cardiomyopathy including one individual in whom the variant was de novo (Tintelen et al., 2007; Fountas et al., 2017; van SpaendonckZwarts et al., 2013; Akinci et al., 2017; Mory et al., 2012). The p.R349W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene LMNA contains 112 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Lipodystrophy (present) , Cardiomyopathy (present) , Kidney disorder (present)
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1A
Familial partial lipodystrophy, Dunnigan type Hutchinson-Gilford syndrome Emery-Dreifuss muscular dystrophy 2, autosomal dominant Emery-Dreifuss muscular dystrophy 2, autosomal dominant Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome Mandibuloacral dysplasia with type A lipodystrophy Charcot-Marie-Tooth disease type 2B1 Heart-hand syndrome, Slovenian type Congenital muscular dystrophy due to LMNA mutation Emery-Dreifuss muscular dystrophy 3, autosomal recessive Restrictive dermopathy 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002815071.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain Significance
(Jun 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004827207.1
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)
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Comment:
This missense variant replaces arginine with tryptophan at codon 349 in the intermediate filament rod domain of the lamin A/C protein. Computational prediction suggests that … (more)
This missense variant replaces arginine with tryptophan at codon 349 in the intermediate filament rod domain of the lamin A/C protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 18035086, 23183350, 23349452, 27813223, 28790152, 31521807) and in individuals affected with unspecified cardiomyopathy (PMID: 28679633, 31383942). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Due to the insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. However, this variant has also been reported in individuals affected with familial partial lipodystrophy, both with and without cardiac involvement (PMID: 22700598, 24080738, 28620495, 28641778, 31794942, 32413188, 32517491, 32939435, 36397776). This variant segregated with disease in multiple individuals affected with familial partial lipodystrophy, both with and without cardiac involvement, in one extended family (PMID: 24080738). It has also been reported in individuals affected with atypical progeroid syndrome with partial lipodystrophy and cardiac abnormalities (PMID: 35384599). Familial partial lipodystrophy is a rare autosomal dominant condition characterized by an abnormal distribution of fatty tissue in the body and associated with metabolic involvement, such as diabetes, hyperlipidemia, and hepatosteatosis, as well as various cardiovascular complications. We recommend you discuss this finding with your healthcare provider. Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause familial partial lipodystrophy (ClinVar variation ID: 66762). (less)
Number of individuals with the variant: 1
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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: SCV000088331.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Benign scapuloperoneal muscular dystrophy with cardiomyopathy
Emery-Dreifuss muscular dystrophy 3, autosomal recessive Charcot-Marie-Tooth disease type 2B1 Limb-girdle muscular dystrophy, type 1B Congenital muscular dystrophy, LMNA-related Dilated cardiomyopathy 1A Dilated cardiomyopathy 1A Hutchinson-Gilford syndrome
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000986842.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as pathogenic and reported on 09/04/2018 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from … (more)
Variant interpretted as pathogenic and reported on 09/04/2018 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Short stature (present) , Abnormality of the curvature of the vertebral column (present) , Joint hypermobility (present)
Age: 20-29 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-09-04
Testing laboratory interpretation: Pathogenic
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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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Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants. | Vasandani C | Journal of the Endocrine Society | 2022 | PMID: 36397776 |
Post-acute cardiac complications following SARS-CoV-2 infection in partial lipodystrophy due to LMNA gene p.R349W mutation. | Ceccarini G | Journal of endocrinological investigation | 2022 | PMID: 35384599 |
Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an LMNA p.R349W Variant. | Hussain I | Journal of the Endocrine Society | 2020 | PMID: 32939435 |
Hypopharyngeal Squamous Cell Carcinoma in Sisters with LMNA Associated Familial Partial Lipodystrophy: A Case Report and Review of the Literature. | Youssef SJ | The Annals of otology, rhinology, and laryngology | 2020 | PMID: 32517491 |
Genotype-phenotype analysis of LMNA-related diseases predicts phenotype-selective alterations in lamin phosphorylation. | Lin EW | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2020 | PMID: 32413188 |
Generation of an integration-free induced pluripotent stem cell line (PUMCHi001-A) from a patient with familial partial lipodystrophy type 2 (FPLD2) carrying a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene. | Xiao C | Stem cell research | 2020 | PMID: 31794942 |
Genetic arrhythmias complicating patients with dilated cardiomyopathy. | Li Z | Heart rhythm | 2020 | PMID: 31521807 |
A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes. | Park J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31383942 |
Lamin A/C-Related Cardiac Disease: Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation. | Hoorntje ET | Circulation. Cardiovascular genetics | 2017 | PMID: 28790152 |
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 |
Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy. | Akinci B | Metabolism: clinical and experimental | 2017 | PMID: 28641778 |
Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T LMNA mutation. | Fountas A | Endocrinology, diabetes & metabolism case reports | 2017 | PMID: 28620495 |
Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy. | Jansweijer JA | European journal of heart failure | 2017 | PMID: 27813223 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Atlas of the clinical genetics of human dilated cardiomyopathy. | Haas J | European heart journal | 2015 | PMID: 25163546 |
Overlapping syndromes in laminopathies: a meta-analysis of the reported literature. | Carboni N | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2013 | PMID: 23853504 |
Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience. | van Spaendonck-Zwarts KY | European journal of heart failure | 2013 | PMID: 23349452 |
Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. | van Rijsingen IA | European journal of heart failure | 2013 | PMID: 23183350 |
Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations. | Mory PB | European journal of endocrinology | 2012 | PMID: 22700598 |
Genotype-phenotype correlations in laminopathies: how does fate translate? | Scharner J | Biochemical Society transactions | 2010 | PMID: 20074070 |
High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. | van Tintelen JP | American heart journal | 2007 | PMID: 18035086 |
Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. | Hermida-Prieto M | The American journal of cardiology | 2004 | PMID: 15219508 |
Diagnostic validity of the MAST and the alcohol dependence scale in the assessment of DSM-III alcohol disorders. | Ross HE | Journal of studies on alcohol | 1990 | PMID: 2270059 |
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Text-mined citations for rs267607555 ...
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.