rs200596619

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_007078.3(LDB3):c.466G>A(p.Ala156Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,612,990 control chromosomes in the GnomAD database, including 3 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A156A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00041 ( 3 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 0.0360

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:

ENSG00000289258 (HGNC:):

ENSG00000289258 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005451441).

BP6

Variant 10-86681580-G-A is Benign according to our data. Variant chr10-86681580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 180399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86681580-G-A is described in Lovd as [Benign]. Variant chr10-86681580-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.466G>A	p.Ala156Thr	missense_variant	5/14	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 linkuse as main transcript	c.321+1423G>A		intron_variant		ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.466G>A	p.Ala156Thr	missense_variant	5/14	1	NM_007078.3	ENSP00000355296.3	O75112-1
ENSG00000289258	ENST00000443292.2 linkuse as main transcript	c.1975G>A	p.Ala659Thr	missense_variant	15/18	1		ENSP00000393132.2	C9JWU6
LDB3	ENST00000263066.11 linkuse as main transcript	c.321+1423G>A		intron_variant		1	NM_001368067.1	ENSP00000263066.7	O75112-6

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000836

AC:

207

AN:

247480

Hom.:

AF XY:

0.000878

AC XY:

118

AN XY:

134430

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00754

Gnomad NFE exome

AF:

0.000342

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000405

AC:

592

AN:

1460704

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

284

AN XY:

726690

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00688

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152286

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00622

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000381

Hom.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000643

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	LDB3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	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.Ala156Thr Based on the data reviewed below we consider this variant a variant of uncertain significance. LIM domain binding 3, also known as LDB3 or ZASP, is a protein which in humans is encoded by the LDB3 gene. Mutations in the LDB3 gene have been reported in patients with autosomal dominant familial dilated cardiomyopathy, however it is currently not known what percentage of individuals with familial DCM have a mutation in the LDB3 gene (Hershberger R et al., 2009). Variants in LDB3 have also been associated with Myofibrillar myopathy (MFM), a morphologically distinct disorder in which disintegration of the Z-disk and then of the myofibrils is followed by abnormal accumulation of multiple proteins. Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Matteo and colleagues studied 100 probands, 15 with identified LVNC. Creatinine kinase levels were normal in all the probands and there was no clinical evidence of a skeletal myopathy. Mutations in ZASP (LDB3) were identified in 6 of the 100 probands, four of whom with identified LVNC and two with DCM (Vatta, M et al., 2003) They did not test other genes associated with DCM and LVNC. No mutations were identified in 200 ethnically matched control individuals (400 chromosomes). Arimurat and colleagues studied ZASP/Cypher gene in 96 unrelated Japanese patients with dilated cardiomyopathy. Five variations were identified in codons -5, 55, 588, 626, 644. They determined V55I and V588I to be polymorphisms because they were also found in unrelated healthy controls. The D626N variation identified in a proband patient of familial DCM was not found in 400 unrelated healthy controls. This variant was shown to alter the function of the LIM domain. They described the phenotype of the family with this variant as having "late onset DCM"; after age 50. No clinical features of LVNC were indicated. Selcen and Engel, 2005 studied ZASP sequence variants in 54 patients with myofibrillar myopathy (MFM) and detected 3 heterozygous missense mutations in 11 patients. Most patients had proximal and distal weakness. Ten carried either of two mutations in exon 6 (A147T and A165V) at or within a motif important in linking ZASP to the Z-disk and one carried a missense mutation in exon 9 (R268C). The A147T variant segregated with disease in 3 additional affected family members. The A165V variant is within, and the A147T mutation is immediately before the ZM motif needed for interaction with actinin. The variants were not present in 220 alleles from control subjects. This variant Ala156Thr is novel and has not been reported as a disease-causing or as a benign polymorphism. The variant p.Ala156Thr is in exon 4 of the LDB3 gene (NM_007078.2) and is within the ZM motif needed for interaction with actinin. This is a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue. In silico analysis with PolyPhen-2 predicts the variant to be benign. Mutation Taster predicts this variant to be a polymorphism. The alanine at codon 156 is NOT conserved across species. Other variants have been reported in association with disease at nearby codons (Ala147Thr; Ala165Val). In total the variant has not been 710 published controls. Ala156Thr is seen in 4 of 8588 European alleles and 0 of 4400 African American alleles in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6,500 Caucasian and African American individuals (as of 7/7/13). This variant is listed in dbSNP (rs200596619). The variant was not observed in the following published contro -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 03, 2020	- -

Myofibrillar myopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Left ventricular noncompaction cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Feb 24, 2014

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2018

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

0.067

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.8

DANN

Benign

0.72

DEOGEN2

Benign

0.18

.;.;T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.60

T;.;T;T;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0055

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.9

N;N;N;.;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.0

N;.;N;N;.;N

REVEL

Benign

0.036

Sift

Benign

0.59

T;.;T;T;.;T

Sift4G

Benign

0.59

T;T;T;T;T;T

Polyphen

0.0, 0.0080

.;.;B;.;B;B

Vest4

0.075

MVP

0.42

MPC

0.19

ClinPred

0.028

GERP RS

-0.66

Varity_R

0.022

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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