10-86681680-C-T

Variant names:

• chr10-86681680-C-T
• rs45487699
• NM_007078.3:c.566C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_007078.3(LDB3):​c.566C>T​(p.Ser189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,613,396 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S189A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:10 B:2
• Conservation: PhyloP100: 3.32
• Publications: 21 publications found

Genes affected

LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

LDB3 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000289258 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3016677).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000519 (79/152358) while in subpopulation AMR AF = 0.000849 (13/15308). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.566C>T	p.Ser189Leu	missense_variant	Exon 5 of 14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.321+1523C>T		intron_variant	Intron 4 of 8	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.566C>T	p.Ser189Leu	missense_variant	Exon 5 of 14	1	NM_007078.3	ENSP00000355296.3
ENSG00000289258	ENST00000443292.2	c.2075C>T	p.Ser692Leu	missense_variant	Exon 15 of 18	1		ENSP00000393132.2
LDB3	ENST00000263066.11	c.321+1523C>T		intron_variant	Intron 4 of 8	1	NM_001368067.1	ENSP00000263066.7

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000649 AC: 162 AN: 249768 AF XY: 0.000679

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000973

Gnomad NFE exome AF: 0.000735

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000591 AC: 863 AN: 1461038 Hom.: 2 Cov.: 32 AF XY: 0.000594 AC XY: 432 AN XY: 726808

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000671 AC: 30 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86226

European-Finnish (FIN) AF: 0.00112 AC: 59 AN: 52788

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000602 AC: 669 AN: 1111882

Other (OTH) AF: 0.000580 AC: 35 AN: 60370

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152358 Hom.: 0 Cov.: 34 AF XY: 0.000537 AC XY: 40 AN XY: 74508

African (AFR) AF: 0.000144 AC: 6 AN: 41590

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000677 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000560 AC: 68

EpiCase AF: 0.000872

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Jul 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDB3 c.566C>T; p.Ser189Leu variant (rs45487699), also known as S196L in the literature, is reported in individuals affected with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy, or ventricular tachycardia (Haas 2014, Khan 2022, Leinonen 2018, Mook 2013, Theis 2006), including one family with four affected relatives (Vatta 2003). This variant is also reported in an individual affected with left ventricular noncompaction (LVNC) with an alternate molecular explanation for disease (Mazzarotto 2021). Functional studies suggest that the p.Ser189Leu variant alters activity of the protein encoded by LDB3, and a mouse model expressing this variant protein in cardiac tissue developed DCM (Arimura 2009 and Li 2010). This variant is also reported in ClinVar (Variation ID: 4731) and is found in the general population with an allele frequency of 0.062% (173/281,154 alleles) in the Genome Aggregation Database (v2.1.1), which is higher than expected for a pathogenic variant in LDB3. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.183). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Arimura et al. Impaired Binding of ZASP/Cypher With Phosphoglucomutase 1 Is Associated With Dilated Cardiomyopathy. Cardiovasc Res. 2009 Jul 1;83(1):80-8. PMID: 19377068. Haas et al. Atlas of the Clinical Genetics of Human Dilated Cardiomyopathy. Eur Heart J. 2015 May 7;36(18):1123-35a. PMID: 25163546. Khan RS et al. Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy. J Am Heart Assoc. 2022 Jan 4;11(1):e022854. PMID: 34935411. Leinonen et al. The Genetics Underlying Idiopathic Ventricular Fibrillation: A Special Role for Catecholaminergic Polymorphic Ventricular Tachycardia? Int J Cardiol. 2018 Jan 1;250:139-145. PMID: 29032884. Li et al. A ZASP Missense Mutation, S196L, Leads to Cytoskeletal and Electrical Abnormalities in a Mouse Model of Cardiomyopathy. Circ Arrhythm Electrophysiol. 2010 Dec;3(6):646-56. PMID: 20852297. Mazzarotto F et al. Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. Genet Med. 2021 May;23(5):856-864. PMID: 33500567. Mook et al. Targeted Sequence Capture and GS-FLX Titanium Sequencing of 23 Hypertrophic and Dilated Cardiomyopathy Genes: Implementation Into Diagnostics. J Med Genet. 2013 Sep;50(9):614-26. PMID: 23785128. Theis et al. Echocardiographic-determined Septal Morphology in Z-disc Hypertrophic Cardiomyopathy. Biochem Biophys Res Commun. 2006 Dec 29;351(4):896-902. PMID: 17097056. Vatta et al. Mutations in Cypher/ZASP in Patients With Dilated Cardiomyopathy and Left Ventricular Non-Compaction. J Am Coll Cardiol. 2003 Dec 3;42(11):2014-27. PMID: 14662268. -

May 30, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDB3: PP2, BP4 -

Jun 02, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Oct 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser189Leu variant in LDB3 has been reported in 2 individuals with HCM and 1 individual with DCM, which segregated with disease in 4 affected relatives (Va tta 2003, Theis 2006, Mook 201). It has been identified by our laboratory in 7 i ndividuals (4 with DCM, 1 with LVNC, 1 with HCM and 1 with RV dilation). Additio nally, in vitro functional studies and a mouse animal model provide some evidenc e that the p.Ser189Leu variant may impact protein function (Arimura 2009, Li 201 0). However, this variant has also been identified in 0.1% (47/65318) of Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs45487699). In summary, while segregation and in vivo evidence s uggest this variant may be disease-causing, its frequency in the ExAC cohort rai ses the possibility that it is not disease causing on its own. Therefore, availa ble evidence for this variant is conflicting and its clinical significance is un certain. -

May 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDB3 c.566C>T (p.Ser189Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 249768 control chromosomes. The observed variant frequency is approximately 25.94 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.566C>T has been reported in the literature in individuals affected with DCM, including 4 affected members of a family (examples: Vatta_2003, Khan_2022. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Experimental evidence has shown the variant to impact protein function (example: Arimura_2009) and mice that expressed the variant developed hemodynamic dysfunction consistent with DCM (Li_2010). The following publications have been ascertained in the context of this evaluation (PMID: 19377068, 34935411, 20852297, 14662268). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as VUS. -

Dilated cardiomyopathy 1C Pathogenic:1

Dec 29, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial hypertrophic cardiomyopathy 24 Pathogenic:1

Dec 29, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 Uncertain:1

Nov 21, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiomyopathy Uncertain:1

Mar 12, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myofibrillar myopathy 4 Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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+1523C>T in the primary transcript. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 189 of the LDB3 protein (p.Ser189Leu). This variant is present in population databases (rs45487699, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic or dilated cardiomyopathy and sudden cardiac death (PMID: 17097056, 23785128, 25163546, 25351510, 35087879). This variant is also known as p.Ser196Leu. ClinVar contains an entry for this variant (Variation ID: 4731). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects LDB3 function (PMID: 19377068, 20852297, 24647531). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

Dilated cardiomyopathy 1A Uncertain:1

Jan 22, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Sep 30, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;.;T;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;.;M;M
PhyloP100		3.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.91	N;.;N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.68	T;.;T;T;.;T
Sift4G	Benign	0.72	T;T;T;T;T;T
Polyphen		0.0020, 0.82, 0.69	.;.;B;.;P;P
Vest4		0.72
MVP		0.74
MPC		0.18
ClinPred		0.032	T
GERP RS		3.8
Varity_R		0.064
gMVP		0.77
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45487699; hg19: chr10-88441437; COSMIC: COSV53943114;