rs138251566

Variant names:

• chr10-86706685-A-G
• rs138251566
• NM_007078.3:c.1051A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_007078.3(LDB3):​c.1051A>G​(p.Thr351Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,612,664 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T351T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: -1.38
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01079753).
• BP6: Variant 10-86706685-A-G is Benign according to our data. Variant chr10-86706685-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36942.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000289 (44/152204) while in subpopulation NFE AF = 0.00053 (36/67978). AF 95% confidence interval is 0.000392. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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.1051A>G	p.Thr351Ala	missense_variant	Exon 8 of 14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.1051A>G	p.Thr351Ala	missense_variant	Exon 8 of 14	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000453 AC: 112 AN: 247106 AF XY: 0.000484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000929

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000614

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000501 AC: 732 AN: 1460460 Hom.: 2 Cov.: 32 AF XY: 0.000512 AC XY: 372 AN XY: 726558

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000806 AC: 36 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52590

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5664

European-Non Finnish (NFE) AF: 0.000568 AC: 631 AN: 1111738

Other (OTH) AF: 0.000580 AC: 35 AN: 60314

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74420

African (AFR) AF: 0.0000482 AC: 2 AN: 41536

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67978

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000616 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.000981

EpiControl AF: 0.000772

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Jun 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr351Ala in exon 10 of LDB3: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including multiple mamm als. In addition, this variant has been identified in 0.08% (27/34356) of Latino and 0.06% (78/124442) of European chromosomes Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org/; dbSNP rs138251566), and in individuals wi th different, non-overlapping cardiomyopathies, including two individuals with a disease-causing variant sufficient to cause their disease (LMM data). -

Nov 20, 2023

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.1051A>G (p.Thr351Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 247106 control chromosomes. The observed variant frequency is approximately 14.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Dilated Cardiomyopathy With Left Ventricular Noncompaction phenotype (3.1e-05), strongly suggesting that the variant is benign. c.1051A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy and ARVC, without strong evidence for causality (Kadiyska_2007, Lopez-Ayala_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: three submitters classified as VUS while five classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Jul 05, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LDB3 p.Thr351Ala Arbustini et al (2007) submitted a brief report to Human Genetics on this variant as a novel variant seen in a 62-year-old male with “noncompaction dilated cardiomyopathy.” I also found a conference abstract in Italian that appears to report the variant in a patient with LVNC (Tripodi et al 2010 71st Congresso Nazionale della Societa Italiana di Cardiologia). A translation via Google translate indicates the authors report the p.Thr351Ala variant in a 41-year old male with LVNC. No segregation or function data was provided in either report. Vatta et al (2003) reported a variant (p.Ile352Met) at the neighboring codon that was present in all five family members with DCM and absent in 200 controls. They predicted that this variant would “abolish an alpha-helix a short beta-sheet.” Another nearby variant (p.Thr350Ile) has been reported in a case of a child with Barth Syndrome (Marziliano et al 2007). That patient also had a nonsense variant in TAZ. Interestingly, the patient’s brother and father both carried the p.Thr350Ile LDB3 variant and had non-compaction on echo, though not severe enough to make diagnostic criteria for LVNC. Arbustini et al (2007) also reported that another patient with “noncompaction dilated cardiomyopathy” had a variant in another nearby codon (p.Thr358Ala). The p.Thr351Ala variant in LDB3 is a non conservative amino acid change with a polar, neutral Threonine replaced with a non polar neutral Alanine. In silico analysis (PolyPhen and SIFT) predicts the variant to be benign and tolerated respectively. While the cases reviewed above do not include HCM, variants in LDB3 have been implicated in HCM. Tripodi et al (2010) did not observe the variant in either 150 or 300 control individuals (difficult to tell in the translated text). No other control data is available, however the variant is not reported in dbSNP (checked March 2nd, 2011) Based on these data, this variant may cause cardiomyopathy, though there is insufficient data available to support predictive genetic testing in at-risk family members. -

not provided Uncertain:1 Benign:1

Mar 04, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with non-compaction dilated cardiomyopathy (Arbustini et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 36942; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31078652, 17438604, 33633783, 23299917, 27896284, 20474083, 25616123, 25041374, 29517769) -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDB3: BP4 -

Dilated cardiomyopathy 1A Uncertain:1

Feb 26, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Aug 11, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myofibrillar myopathy 4 Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LDB3-related disorder Benign:1

May 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypertrophic cardiomyopathy Benign:1

Mar 16, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The LDB3 Thr351Ala has been reported before in an an ARVD/C proband, and was found to cosegregate to two siblings diagnosed with ARVD/C (Lopez JM, et al., 2014). This variant has also been found in a 62yo male patient with severe dilated cardiomyopathy with non-compaction (Arbustini E, et al., 2007) and a HCM patient with another likely causal variant (LMM ClinVar; SCV000062395.4). It is present in the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), at an allele frequency >0.0004, which is higher then expected for an inherited heart disease. We identified this variant in a HCM proband with no family history of HCM or SCD. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be non-deleterious. In summary, based on a high allele frequency in the general population and in silico tools predicting no functional affect on the protein, we classify LDB3 Thr351Ala as "likely benign". -

Cardiovascular phenotype Benign:1

Mar 23, 2020

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	0.053
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.029
DANN	Benign	0.34
DEOGEN2	Benign	0.17	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.055	N
PhyloP100		-1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.46
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.059
MVP		0.53
ClinPred		0.013	T
GERP RS		-9.3
Varity_R		0.023
Mutation Taster		=38/62	disease causing

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: rs138251566; hg19: chr10-88466442;