ClinVar Genomic variation as it relates to human health
NM_007078.3(LDB3):c.655C>T (p.Arg219Ter)
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(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007078.3(LDB3):c.655C>T (p.Arg219Ter)
Variation ID: 163829 Accession: VCV000163829.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.2 10: 86681769 (GRCh38) [ NCBI UCSC ] 10: 88441526 (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 Feb 13, 2018 Feb 14, 2024 Oct 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007078.3:c.655C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009009.1:p.Arg219Ter nonsense NM_001368067.1:c.321+1612C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001080114.2:c.321+1612C>T intron variant NM_001080115.2:c.655C>T NP_001073584.1:p.Arg219Ter nonsense NM_001080116.1:c.321+1612C>T intron variant NM_001171610.2:c.655C>T NP_001165081.1:p.Arg219Ter nonsense NM_001171611.2:c.655C>T NP_001165082.1:p.Arg219Ter nonsense NM_001368063.1:c.655C>T NP_001354992.1:p.Arg219Ter nonsense NM_001368064.1:c.655C>T NP_001354993.1:p.Arg219Ter nonsense NM_001368065.1:c.655C>T NP_001354994.1:p.Arg219Ter nonsense NM_001368066.1:c.321+1612C>T intron variant NM_001368068.1:c.321+1612C>T intron variant NC_000010.11:g.86681769C>T NC_000010.10:g.88441526C>T NG_008876.1:g.18206C>T LRG_385:g.18206C>T LRG_385t1:c.655C>T LRG_385t2:c.321+1612C>T - Protein change
- R219*
- Other names
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- Canonical SPDI
- NC_000010.11:86681768: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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LDB3 | - | - |
GRCh38 GRCh37 |
1168 | 1347 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 17, 2023 | RCV000150918.7 | |
Uncertain significance (3) |
criteria provided, single submitter
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Jul 21, 2023 | RCV000766441.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 17, 2023 | RCV001242445.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 30, 2021 | RCV002466447.1 |
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
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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
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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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Uncertain significance
(Apr 16, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198544.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 13, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The Arg219X var iant in LDB3 has not been reported in individuals with cardiomyopathy or in larg … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The Arg219X var iant in LDB3 has not been reported in individuals with cardiomyopathy or in larg e population studies. This nonsense variant leads to a premature termination cod on at position 219, which is predicted to lead to a truncated or absent protein (loss-of-function). Studies of mouse models support that absence of LDB3 in the heart leads to DCM (Zheng 2009); however, this has not been well studied in huma ns. Our laboratory has detected homozygous/compound heterozygous loss-of-functio n variants in LDB3 in 2 neonates with DCM +/- LVNC and 1 individual with VT and SCA carried heterozygous loss of function variant. These data suggest that loss- of-function variants in LDB3 are pathogenic in the homozygous/compound heterozyg ous state but additional studies are needed to fully establish their clinical si gnificance. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1C
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761785.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Uncertain significance
(Jul 21, 2023)
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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: SCV000680933.4
First in ClinVar: Feb 13, 2018 Last updated: Aug 13, 2023 |
Comment:
In an abstract by Gotway et al., 2023, the p.(R219X) variant was identified in trans with a second nonsense variant in the LDB3 gene in … (more)
In an abstract by Gotway et al., 2023, the p.(R219X) variant was identified in trans with a second nonsense variant in the LDB3 gene in two brothers with LVNC as newborns that improved over time; Identified in a control patient with hypertension-related cardiac hypertrophy (Holmstrom et al., 2021); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not an established mechanism of disease; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 34045587) (less)
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Uncertain significance
(Oct 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004121754.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: LDB3 c.655C>T (p.Arg219X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: LDB3 c.655C>T (p.Arg219X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in LDB3 as causative of disease. The variant allele was found at a frequency of 3.7e-05 in 241230 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. An alternate transcript is also associated with this variant: NM_001080116 c.321+1612C>T. c.655C>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy and alcoholic cardiomyopathy, without evidence of causation (Ware_2018, Holmstrom_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34045587, 34691145, 29773157). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Pathogenic
(Aug 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 4
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001415532.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 163829). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. This variant is present in population databases (rs727503123, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg219*) in the LDB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDB3 are known to be pathogenic (PMID: 36253531). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.321+1612C>T in the primary transcript. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958194.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964623.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy. | Koopmann TT | European journal of human genetics : EJHG | 2023 | PMID: 36253531 |
Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region. | Ramensky VE | Frontiers in genetics | 2021 | PMID: 34691145 |
Genetic contributions to the expression of acquired causes of cardiac hypertrophy in non-ischemic sudden cardiac death victims. | Holmström L | Scientific reports | 2021 | PMID: 34045587 |
Genetic Etiology for Alcohol-Induced Cardiac Toxicity. | Ware JS | Journal of the American College of Cardiology | 2018 | PMID: 29773157 |
Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death. | Zheng M | Human molecular genetics | 2009 | PMID: 19028670 |
Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy. | Zhou Q | The Journal of cell biology | 2001 | PMID: 11696561 |
Text-mined citations for rs727503123 ...
HelpRecord last updated Feb 20, 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.