NM_007078.3:c.1594G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B.

-7

BP4_ModerateBP6BS1

The NM_007078.3(LDB3):c.1594G>C(p.Ala532Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000643 in 1,613,876 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 4.21

Publications

6 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08732876).

BP6

Variant 10-86716689-G-C is Benign according to our data. Variant chr10-86716689-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201852.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000381 (58/152228) while in subpopulation NFE AF = 0.000721 (49/68002). AF 95% confidence interval is 0.00056. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.1594G>C	p.Ala532Pro	missense_variant	Exon 10 of 14	ENST00000361373.9	NP_009009.1	O75112-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 link	c.1594G>C	p.Ala532Pro	missense_variant	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3		O75112-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000720

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000348

AC:

AN:

250332

AF XY:

0.000332

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000709

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000670

AC:

980

AN:

1461648

Hom.:

Cov.:

AF XY:

0.000624

AC XY:

454

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000817

AC:

908

AN:

1111990

Other (OTH)

AF:

0.00109

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.000381

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41542

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000721

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000447

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDB3: BS1 -

Apr 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDB3 c.1594G>C; p.Ala532Pro variant (rs143764931) is reported in the literature in a cohort of individuals affected with hypertrophic cardiomyopathy, though it was not demonstrated to cause disease (Lopes 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.07% (85/128298 alleles) in the Genome Aggregation Database. The alanine at codon 532 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.244). Given the lack of clinical and functional data, the significance of the p.Ala532Pro variant is uncertain at this time. References: Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. PMID: 25351510. -

Sep 18, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with HCM (Lopes et al., 2015); however, no specific clinical details were provided; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 201852; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25351510) -

not specified

Benign:1

Jan 08, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ala532Pro variant in LDB3 is classified as likely benign because it has been identified in 0.07% (85/128298) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org; dbSNP rs143764931). In addition, alanine (Ala) at position 532 is not conserved in evolution and proline (Pro) is present at this position in >10 bird and reptile species. ACMG/AMP Criteria applied: BS1. -

Cardiomyopathy

Benign:1

Mar 26, 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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial isolated dilated cardiomyopathy

Benign:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (92 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported once in a hypertropic cardiomyopathy cohort study (PMID: 23396983), and has also been previously observed twice in our HCM patient cohort and once in our ARVC patient cohort in patients harbouring pathogenic variants. Additionally, it has been reported as VUS and likely benign in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype

Benign:1

May 16, 2022

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

0.092

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

.;.;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;.;D;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.087

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.4

.;.;M;.

PhyloP100

4.2

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

N;.;N;N

REVEL

Benign

0.24

Sift

Benign

0.070

T;.;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.047, 1.0

.;.;B;D

Vest4

0.18

MVP

0.83

MPC

0.40

ClinPred

0.063

GERP RS

4.8

Varity_R

0.42

gMVP

0.55

Mutation Taster

=49/51

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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