10-86716476-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007078.3(LDB3):c.1381T>G(p.Tyr461Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,392,288 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y461S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.49

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24981874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.1381T>G	p.Tyr461Asp	missense_variant	Exon 10 of 14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 link	c.1381T>G	p.Tyr461Asp	missense_variant	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes

AF:

0.0000151

AC:

AN:

132302

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000563

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000159

AC:

AN:

1259986

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

624784

show subpopulations

African (AFR)

AF:

0.0000727

AC:

AN:

27518

American (AMR)

AF:

0.00

AC:

AN:

38670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18448

East Asian (EAS)

AF:

0.00

AC:

AN:

20798

South Asian (SAS)

AF:

0.00

AC:

AN:

84364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

981104

Other (OTH)

AF:

0.00

AC:

AN:

46950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000151

AC:

AN:

132302

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

63430

show subpopulations

African (AFR)

AF:

0.0000563

AC:

AN:

35510

American (AMR)

AF:

0.00

AC:

AN:

12594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3286

East Asian (EAS)

AF:

0.00

AC:

AN:

3906

South Asian (SAS)

AF:

0.00

AC:

AN:

3578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62662

Other (OTH)

AF:

0.00

AC:

AN:

1774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

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:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 01, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Reported using an alternate transcript of the gene; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jun 21, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Gene-level evidence for LDB3 and LVNC There is limited evidence linking the LDB3 gene to LVNC. Vatta et al., 2003 reported LDB3 variants via candidate gene screening in 6 of 100 probands with a DCM, DCM/LVNC, and LVNC spectrum of phenotypes. We have seen this variant in one individual with LVNC. Testing was done through Invitae. Given the lack of case data we consider this variant to be of unknown significance and we do not currently feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). However, this variant is of interest, as it is located in an exon that is preferentially expressed in the heart and has been reported to be involved in other cases of cardiomyopathy. Tyr461Asp There is no case data for this variant. It has not been published as a disease-causing variant in LVNC, or other cardiomyopathies or phenotypes. Invitae reports that in silico analyses (SIFT, PolyPhen-2, Align-GVD) predict this variant to be disruptive. Mutation Taster predicted it to be a polymorphism. The Tyrosine at codon 461 is not well conserved across species, though there are large physicochemical difference between tyrosine and asparagine. The variant was reported online in 1 of of 59,814 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 3/2016). Specifically, the variant was observed in 1 of 5,094 African individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Myofibrillar myopathy 4

Uncertain:1

Oct 22, 2024

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_007078.2, and corresponds to NM_001080116.1:c.*17102T>G in the primary transcript. This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 461 of the LDB3 protein (p.Tyr461Asp). This variant is present in population databases (rs145655904, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. 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 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y461D variant (also known as c.1381T>G), located in coding exon 9 of the LDB3 gene, results from a T to G substitution at nucleotide position 1381. The tyrosine at codon 461 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

.;.;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.92

D;.;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.7

.;.;M;.

PhyloP100

1.5

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.15

Sift

Benign

0.13

T;.;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.96, 0.36

.;.;D;B

Vest4

0.39

MutPred

0.33

.;.;Loss of catalytic residue at Y461 (P = 0.0026);.;

MVP

0.77

MPC

0.37

ClinPred

0.38

GERP RS

4.3

Varity_R

0.19

gMVP

0.50

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

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

Publications

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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