VCV000518946.27 - ClinVar

NM_001368067.1(LDB3):c.433G>A (p.Gly145Ser)

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.

(8)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001368067.1(LDB3):c.433G>A (p.Gly145Ser)

Variation ID: 518946 Accession: VCV000518946.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.2 10: 86687157 (GRCh38) [ NCBI UCSC ] 10: 88446914 (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	Apr 14, 2018	May 1, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007078.3:c.690-4739G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001368067.1:c.433G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001354996.1:p.Gly145Ser	missense
NM_001080114.2:c.433G>A	NP_001073583.1:p.Gly145Ser	missense
NM_001080115.2:c.690-4739G>A		intron variant
NM_001080116.1:c.433G>A	NP_001073585.1:p.Gly145Ser	missense
NM_001171610.2:c.778G>A	NP_001165081.1:p.Gly260Ser	missense
NM_001171611.2:c.778G>A	NP_001165082.1:p.Gly260Ser	missense
NM_001368063.1:c.690-4739G>A		intron variant
NM_001368064.1:c.690-4739G>A		intron variant
NM_001368065.1:c.690-4739G>A		intron variant
NM_001368066.1:c.433G>A	NP_001354995.1:p.Gly145Ser	missense
NM_001368068.1:c.433G>A	NP_001354997.1:p.Gly145Ser	missense
NM_007078.2:c.690-4739G>A
NC_000010.11:g.86687157G>A
NC_000010.10:g.88446914G>A
NG_008876.1:g.23594G>A
NG_054099.1:g.3186G>A
LRG_385:g.23594G>A
LRG_385t2:c.433G>A	LRG_385p2:p.Gly145Ser

... more HGVS ... less HGVS

Protein change

G145S, G260S

Other names

Canonical SPDI

NC_000010.11:86687156: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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00007

The Genome Aggregation Database (gnomAD) 0.00009

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016

Links

ClinGen: CA5584823 dbSNP: rs376489385 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.
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Oct 20, 2016	RCV000618434.4
Primary dilated cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 3, 2019	RCV000853126.2
not provided	Uncertain significance (4)	criteria provided, single submitter	Dec 23, 2021	RCV001509393.10
Myofibrillar myopathy 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 8, 2024	RCV000661930.13

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 (Jul 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Primary dilated cardiomyopathy Affected status: yes Allele origin: germline	Klaassen Lab, Charite University Medicine Berlin Accession: SCV000995838.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Publications: PubMed (2) PubMed: 31568572‚ 31333075
Uncertain significance (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myofibrillar myopathy 4 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784255.2 First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 40-49 years Sex: female Geographic origin: Iran
Uncertain significance (Jan 08, 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: SCV000945451.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 31737537‚ 36178741 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 145 of the LDB3 protein (p.Gly145Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 145 of the LDB3 protein (p.Gly145Ser). This variant is present in population databases (rs376489385, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 31737537, 36178741). ClinVar contains an entry for this variant (Variation ID: 518946). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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 (Oct 20, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000736688.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: The p.G145S variant (also known as c.433G>A), located in coding exon 5 of the LDB3 gene, results from a G to A substitution at nucleotide … (more) The p.G145S variant (also known as c.433G>A), located in coding exon 5 of the LDB3 gene, results from a G to A substitution at nucleotide position 433. The glycine at codon 145 is replaced by serine, an amino acid with similar properties. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/12806) total alleles studied and 0.02% (2/8498) European American alleles. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (5/105598). 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)
Uncertain significance (Dec 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001716077.2 First in ClinVar: Jun 15, 2021 Last updated: Sep 20, 2023
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001954029.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (-)	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: SCV001971163.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035165.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 145 of the LDB3 protein (p.Gly145Ser). This variant is present in population databases (rs376489385, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 31737537, 36178741). ClinVar contains an entry for this variant (Variation ID: 518946). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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:

The p.G145S variant (also known as c.433G>A), located in coding exon 5 of the LDB3 gene, results from a G to A substitution at nucleotide position 433. The glycine at codon 145 is replaced by serine, an amino acid with similar properties. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/12806) total alleles studied and 0.02% (2/8498) European American alleles. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (5/105598). 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.

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
Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification.	van der Meulen MH	Circulation. Genomic and precision medicine	2022	PMID: 36178741
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders.	Marschall C	Cardiovascular diagnosis and therapy	2019	PMID: 31737537
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3.	Kühnisch J	Clinical genetics	2019	PMID: 31568572
RIKADA Study Reveals Risk Factors in Pediatric Primary Cardiomyopathy.	Al-Wakeel-Marquard N	Journal of the American Heart Association	2019	PMID: 31333075

Text-mined citations for rs376489385 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001368067.1(LDB3):c.433G>A (p.Gly145Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs376489385 ...