rs35507268

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007078.3(LDB3):c.352G>A(p.Val118Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,606,432 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0061 ( 32 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.0900

Publications

15 publications found

Variant links:

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

LDB3 links:

ENSG00000289258 (HGNC:):

ENSG00000289258 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005024433).

BP6

Variant 10-86681466-G-A is Benign according to our data. Variant chr10-86681466-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00394 (601/152364) while in subpopulation NFE AF = 0.00591 (402/68034). AF 95% confidence interval is 0.00543. There are 2 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.352G>A	p.Val118Met	missense_variant	Exon 5 of 14	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 link	c.321+1309G>A		intron_variant	Intron 4 of 8	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LDB3	ENST00000361373.9 link	c.352G>A	p.Val118Met	missense_variant	Exon 5 of 14	1	NM_007078.3	ENSP00000355296.3	O75112-1
ENSG00000289258	ENST00000443292.2 link	c.1861G>A	p.Val621Met	missense_variant	Exon 15 of 18	1		ENSP00000393132.2	C9JWU6
LDB3	ENST00000263066.11 link	c.321+1309G>A		intron_variant	Intron 4 of 8	1	NM_001368067.1	ENSP00000263066.7	O75112-6

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00414

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00591

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00432

AC:

1042

AN:

241370

AF XY:

0.00434

show subpopulations

Gnomad AFR exome

AF:

0.000959

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00593

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00501

Gnomad NFE exome

AF:

0.00685

Gnomad OTH exome

AF:

0.00416

GnomAD4 exome

AF:

0.00614

AC:

8934

AN:

1454068

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

4377

AN XY:

723726

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33456

American (AMR)

AF:

0.00186

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00613

AC:

160

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000916

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00514

AC:

237

AN:

46120

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00728

AC:

8095

AN:

1111780

Other (OTH)

AF:

0.00419

AC:

253

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

585

1171

1756

2342

2927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00394

AC:

601

AN:

152364

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

296

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41592

American (AMR)

AF:

0.00509

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00591

AC:

402

AN:

68034

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00581

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00458

AC:

553

EpiCase

AF:

0.00534

EpiControl

AF:

0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 06, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 03, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val118Met in exon 4 of LDB3: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (455/63354) of European chromos omes including 1 homozygous individual by the Exome Aggregation Consortium (http ://exac.broadinstitute.org/; dbSNP rs35507268). -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 02, 2015

Blueprint Genetics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDB3: BP4, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:2

Feb 26, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 17, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Benign:1

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myofibrillar myopathy 4

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LDB3-related disorder

Benign:1

Oct 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Cardiovascular phenotype

Benign:1

May 21, 2018

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

0.10

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;.;T;T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.073

LIST_S2

Uncertain

0.90

D;.;D;D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.0050

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;L;.;L;L

PhyloP100

0.090

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.53

N;.;N;N;.;N

REVEL

Benign

0.022

Sift

Benign

0.17

T;.;T;T;.;D

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.0010, 0.49, 0.42

.;.;B;.;P;B

Vest4

0.22

MVP

0.62

MPC

0.20

ClinPred

0.0053

GERP RS

0.30

Varity_R

0.039

gMVP

0.26

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over