ENST00000477489.1:c.232G>A

Variant names:

• chr10-86726250-G-A
• rs45577134
• ENST00000477489.1:c.232G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS1

The ENST00000477489.1(LDB3):​c.232G>A​(p.Ala78Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,613,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A78S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: LDB3 ENST00000477489.1 missense
• Scores: Splicing: ADA: 0.9587
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 10.0
• Publications: 20 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

ENSG00000272631 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 10-86726250-G-A is Benign according to our data. Variant chr10-86726250-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36446.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000236 (36/152264) while in subpopulation NFE AF = 0.000265 (18/68024). AF 95% confidence interval is 0.000171. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.2092G>A	p.Ala698Thr	missense_variant, splice_region_variant	Exon 13 of 14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.2092G>A	p.Ala698Thr	missense_variant, splice_region_variant	Exon 13 of 14	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000235 AC: 59 AN: 251374 AF XY: 0.000243

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000522 AC: 762 AN: 1460740 Hom.: 0 Cov.: 30 AF XY: 0.000472 AC XY: 343 AN XY: 726738

African (AFR) AF: 0.000209 AC: 7 AN: 33458

American (AMR) AF: 0.0000895 AC: 4 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.000652 AC: 724 AN: 1111012

Other (OTH) AF: 0.000265 AC: 16 AN: 60356

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74438

African (AFR) AF: 0.000241 AC: 10 AN: 41564

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68024

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Jul 07, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDB3 c.2092G>A (p.Ala698Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 251374 control chromosomes. The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Dilated Cardiomyopathy phenotype (3.1e-05). c.2092G>A has been observed in individual(s) affected with Dilated Cardiomyopathy, without strong evidence for causality (Andreasen_2013, Haas_2015, Hershberger_2008, Li_2010, vanderMeulen_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported ( MYH7 c.709C>T , p.Arg237Trp), providing supporting evidence for a benign role (Hershberger_2008). 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: 23299917, 25163546, 19412328, 20590677, 36178741). ClinVar contains an entry for this variant (Variation ID: 36446). Based on the evidence outlined above, the variant was classified as likely benign. -

Aug 01, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala698Thr variant in LDB3 has been reported in 2 individuals with DCM, both of whom also carry an additional variant in another cardiomyopathy-associated ge ne (Hershberger 2008, Li 2010). This variant has also been identified by our lab oratory in 1 Native American individual with HCM and 1 African American infant w ith DCM. This variant has been identified in 6/8600 European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs45577134). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, the clinical significance of the Ala698Thr variant is uncertain. -

not provided Benign:2

Oct 31, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19412328, 20590677, 22337857, 23299917, 25163546, 30547036) -

Cardiomyopathy Uncertain:1

May 25, 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 26, 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.*26876G>A in the primary transcript. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 698 of the LDB3 protein (p.Ala698Thr). This variant is present in population databases (rs45577134, gnomAD 0.04%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19412328, 20590677, 25163546). This variant is also known as c.G1762A (p.A588T). ClinVar contains an entry for this variant (Variation ID: 36446). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Cardiovascular phenotype Uncertain:1

Sep 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A698T variant (also known as c.2092G>A), located in coding exon 12 of the LDB3 gene, results from a G to A substitution at nucleotide position 2092. The alanine at codon 698 is replaced by threonine, an amino acid with similar properties. This alteration was reported in two unrelated probands with dilated cardiomyopathy (DCM); however, both carried variants in other DCM-associated genes (Hershberger RE et al. Clin Transl Sci. 2008;1:21-6; Li D et al. Clin Transl Sci. 2010;3:90-7). This alteration has also been detected in DCM and cardiomyopathy genetic testing cohorts (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been detected in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet. 2013;21:918-28). 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. -

Dilated cardiomyopathy 1C Benign:1

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (67 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in the annotated LIM zinc-binding 3 domain. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Ala703Ser) has one VUS entry in ClinVar. (N) 0806 - Moderate previous evidence of neutrality in unrelated individuals. Identified in multiple patients at VCGS with LQTS and Brugada syndrome. This variant has six VUS and one likely benign entry in ClinVar. (B) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) – Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0072	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	.;.;D;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Uncertain	0.095	D
MutationAssessor	Benign	1.1	.;.;L;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N;.;N;N;.
REVEL	Uncertain	0.55
Sift	Benign	0.077	T;.;T;T;.
Sift4G	Benign	0.063	T;T;T;T;T
Polyphen		0.99, 1.0	.;.;D;D;.
Vest4		0.81
MVP		0.94
MPC		0.75
ClinPred		0.21	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.60
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.82
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: rs45577134; hg19: chr10-88486007;