VCV000004733.47 - ClinVar

NM_001368067.1(LDB3):c.349G>A (p.Asp117Asn)

Germline

Classification

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.

(20)

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(1); Benign(11); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001368067.1(LDB3):c.349G>A (p.Asp117Asn)

Variation ID: 4733 Accession: VCV000004733.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.2 10: 86687073 (GRCh38) [ NCBI UCSC ] 10: 88446830 (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	Jun 4, 2015	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007078.3:c.690-4823G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001368067.1:c.349G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001354996.1:p.Asp117Asn	missense
NM_001080114.2:c.349G>A	NP_001073583.1:p.Asp117Asn	missense
NM_001080115.2:c.690-4823G>A		intron variant
NM_001080116.1:c.349G>A	NP_001073585.1:p.Asp117Asn	missense
NM_001171610.2:c.694G>A	NP_001165081.1:p.Asp232Asn	missense
NM_001171611.2:c.694G>A	NP_001165082.1:p.Asp232Asn	missense
NM_001368063.1:c.690-4823G>A		intron variant
NM_001368064.1:c.690-4823G>A		intron variant
NM_001368065.1:c.690-4823G>A		intron variant
NM_001368066.1:c.349G>A	NP_001354995.1:p.Asp117Asn	missense
NM_001368068.1:c.349G>A	NP_001354997.1:p.Asp117Asn	missense
NC_000010.11:g.86687073G>A
NC_000010.10:g.88446830G>A
NG_008876.1:g.23510G>A
NG_054099.1:g.3102G>A
LRG_385:g.23510G>A
LRG_385t1:c.690-4823G>A
LRG_385t2:c.349G>A	LRG_385p2:p.Asp117Asn

... more HGVS ... less HGVS

Protein change

D117N, D232N

Other names

p.D232N:GAC>AAC
LDB3, ASP117ASN (rs121908338)

Canonical SPDI

NC_000010.11:86687072:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00779 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00584

1000 Genomes Project 0.00779

1000 Genomes Project 30x 0.00812

Trans-Omics for Precision Medicine (TOPMed) 0.00821

Links

ClinGen: CA249992 OMIM: 605906.0007 dbSNP: rs121908338 VarSome

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
Gene	OMIM	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.
LDB3		-	-	GRCh38 GRCh37	1207	1387
LOC110121486	-	-	-	GRCh38	-	135

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.
Dilated cardiomyopathy 1C	Uncertain significance (2)	criteria provided, single submitter	Apr 27, 2017	RCV000004998.16
not specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Jan 2, 2020	RCV000036845.28
Primary dilated cardiomyopathy	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 28, 2017	RCV000172755.11
not provided	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000224167.30
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jan 11, 2016	RCV000618022.11
Myofibrillar myopathy 4	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV000234167.15

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.
Benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Cardiomyopathy, dilated Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000051395.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 5
Likely Benign (Apr 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281105.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000306367.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jan 23, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230992.5 First in ClinVar: Jun 28, 2015 Last updated: Oct 02, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LDB3 Number of individuals with the variant: 1 Sex: mixed
Benign (Aug 07, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060500.5 First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016	Publications: PubMed (2) PubMed: 14662268‚ 22929165 Comment: Asp117Asn in exon 6 of LDB3: This variant is not expected to have clinical signi ficance because it has been identified in 1.3% (51/4090) of … (more) Asp117Asn in exon 6 of LDB3: This variant is not expected to have clinical signi ficance because it has been identified in 1.3% (51/4090) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs121908338). It has been reported in 2 individu als with DCM and 1 individual with LVNC (Vatta 2002, Xi 2012). In vitro studies suggest that it may have functional consequences (Xi 2012), though it should be noted that in vitro studies may not accurately represent biological function and /or may not translate to disease. In summary, the frequency of this variant in the general population suggests that it does not cause disease on its own. It re mains possible that it modifies disease expression. (less) Number of individuals with the variant: 43
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001265379.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Dec 03, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170110.10 First in ClinVar: Jul 05, 2015 Last updated: Oct 02, 2016	Comment: This variant is associated with the following publications: (PMID: 14662268, 26636822, 26419279, 28416588, 22929165, 23299917, 22995991, 22619057, 27884173, 27896284, 30293248, 30972196, 25214167)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Myofibrillar myopathy 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000289629.5 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Benign (Oct 26, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001471544.3 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004033061.11 First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024	Comment: LDB3: BP4, BS1, BS2 Number of individuals with the variant: 11
Benign (Feb 28, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995322.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Benign (Jan 02, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001476527.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (10) PubMed: 26419279‚ 26636822‚ 27561770‚ 27896284‚ 14662268‚ 22619057‚ 22929165‚ 22995991‚ 23299917‚ 22464770
Benign (Jan 11, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000735294.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Dec 03, 2003)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025174.4 First in ClinVar: Apr 04, 2013 Last updated: Jul 15, 2016	Publications: PubMed (2) PubMed: 26419279‚ 14662268 Comment on evidence: This variant, formerly titled CARDIOMYOPATHY, DILATED, 1C, WITH LEFT VENTRICULAR NONCOMPACTION, has been reclassified based on the findings of Levitas et al. (2016). In 2 … (more) This variant, formerly titled CARDIOMYOPATHY, DILATED, 1C, WITH LEFT VENTRICULAR NONCOMPACTION, has been reclassified based on the findings of Levitas et al. (2016). In 2 unrelated sporadic cases of dilated cardiomyopathy with left ventricular noncompaction (CMD1C; 601493), Vatta et al. (2003) identified heterozygosity for a 349G-A transition in exon 6 of the LDB3 gene, resulting in an asp117-to-asn (D117N) mutation. One patient was a 44-year-old female, diagnosed at 41 years of age with DCM, heart failure, left bundle branch block, and dilated left ventricle with deep trabeculations. The other was a 33-year-old male, diagnosed with DCM at 30 years of age during a family echocardiographic screen after sudden death had occurred within the family. Echocardiographic and MRI screening identified both left and right ventricular trabeculations, with severe left ventricular hypertrophy, an intraventricular conduction delay, and ventricular bigeminy on electrocardiogram, as well as echocardiographic evidence of borderline systolic function and a dilated left ventricle. In the other family members, neither DCM nor isolated noncompaction of the left ventricular myocardium was identified. Levitas et al. (2016) studied 2 large Bedouin Israeli families segregating autosomal dominant CMD and ventricular arrhythmias, with focal LVNC in some patients of the first family and apical trabeculations compatible with a mild variant of LVNC in some patients of the second family. Analysis of 100 cardiomyopathy-associated genes revealed only 1 putative mutation, the D117N variant in the LDB3 gene. However, the variant was present in only 6 of 16 genotyped patients, and was also detected in 5 healthy family members who were thoroughly evaluated. In addition, there was no apparent correlation between disease severity and the presence of D117N. Analysis of the prevalence of the variant in unrelated individuals from the general Bedouin population from the same region of southern Israel revealed it to be present in heterozygosity in 11 (5.2%) of 210 chromosomes, which was much higher than the incidence of idiopathic CMD in that population. The authors also noted that this variant has a prevalence of 0.65% and 1% in the 1000 Genomes Project and ClinSeq databases, respectively, and is present at 0.3% in European Americans and 1.2% in African Americans in the Exome Variant Server database. Levitas et al. (2016) concluded that, at least in the Bedouin population, D117N is not the causative mutation for these cardiac abnormalities, and suggested that it may not be causative in other patients as well. (less)
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: SCV001917870.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930144.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001966188.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740939.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	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: SCV001951300.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV002036194.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

Asp117Asn in exon 6 of LDB3: This variant is not expected to have clinical signi ficance because it has been identified in 1.3% (51/4090) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs121908338). It has been reported in 2 individu als with DCM and 1 individual with LVNC (Vatta 2002, Xi 2012). In vitro studies suggest that it may have functional consequences (Xi 2012), though it should be noted that in vitro studies may not accurately represent biological function and /or may not translate to disease. In summary, the frequency of this variant in the general population suggests that it does not cause disease on its own. It re mains possible that it modifies disease expression.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy.	Nouhravesh N	Molecular genetics & genomic medicine	2016	PMID: 27896284
Left Ventricular Noncompaction: A Distinct Genetic Cardiomyopathy?	Arbustini E	Journal of the American College of Cardiology	2016	PMID: 27561770
D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.	Levitas A	European journal of human genetics : EJHG	2016	PMID: 26419279
Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel.	Celestino-Soper PB	PloS one	2015	PMID: 26636822
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.	Andreasen C	European journal of human genetics : EJHG	2013	PMID: 23299917
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction.	Xi Y	Circulation. Arrhythmia and electrophysiology	2012	PMID: 22929165
ZASPopathy with childhood-onset distal myopathy.	Strach K	Journal of neurology	2012	PMID: 22619057
Genetic testing for dilated cardiomyopathy in clinical practice.	Lakdawala NK	Journal of cardiac failure	2012	PMID: 22464770
Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.	Vatta M	Journal of the American College of Cardiology	2003	PMID: 14662268
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LDB3	-	-	-	-
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Text-mined citations for rs121908338 ...

These 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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001368067.1(LDB3):c.349G>A (p.Asp117Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908338 ...