10-86716567-T-A

Position:

chr10-86716567-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_007078.3(LDB3):c.1472T>A(p.Val491Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,014 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 (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.60

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 links:

LDB3 (HGNC:):

LDB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27645648).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.1472T>A	p.Val491Glu	missense_variant	10/14	ENST00000361373.9	NP_009009.1	O75112-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.1472T>A	p.Val491Glu	missense_variant	10/14	1	NM_007078.3	ENSP00000355296.3		O75112-1

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000977

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249360

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134982

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000331

AC:

AN:

151174

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73796

show subpopulations

Gnomad4 AFR

AF:

0.0000974

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 11, 2012

The Val491Glu variant (LDB3) has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Val 491Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant has been identified in 0.03% (1 /3738) of African American chromosomes from a broad population by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs139709036). In summary, additional information is needed to fully assess the clinical signific ance of the Val491Glu variant. -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

Myofibrillar myopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17193T>A in the primary transcript. This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 491 of the LDB3 protein (p.Val491Glu). This variant is present in population databases (rs139709036, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2021

The p.V491E variant (also known as c.1472T>A), located in coding exon 9 of the LDB3 gene, results from a T to A substitution at nucleotide position 1472. The valine at codon 491 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been detected in the homozygous state in an individual with pediatric-onset dilated cardiomyopathy who also had additional variants in LDB3 in addition to variants in other cardiac-related genes (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Walsh R et al. Genet Med, 2017 02;19:192-203), and has also been detected in an exome cohort (referred to as c.1142T>A, p.V381E); however, details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Benign

0.86

DEOGEN2

Uncertain

0.78

.;.;D;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;.;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.7

.;.;M;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.5

N;.;D;N

REVEL

Benign

0.20

Sift

Benign

0.067

T;.;D;D

Sift4G

Benign

0.073

T;T;D;T

Polyphen

0.97, 0.81

.;.;D;P

Vest4

0.61

MVP

0.84

MPC

0.97

ClinPred

0.28

GERP RS

4.0

Varity_R

0.43

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over