rs139922045

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_007078.3(LDB3):c.664G>A(p.Ala222Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,598,880 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 2.84

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05650574).

BP6

Variant 10-86681778-G-A is Benign according to our data. Variant chr10-86681778-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45551.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000348 (53/152342) while in subpopulation NFE AF = 0.000764 (52/68036). AF 95% confidence interval is 0.000598. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.664G>A	p.Ala222Thr	missense_variant	Exon 5 of 14	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 link	c.321+1621G>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.664G>A	p.Ala222Thr	missense_variant	Exon 5 of 14	1	NM_007078.3	ENSP00000355296.3	O75112-1
ENSG00000289258	ENST00000443292.2 link	c.2173G>A	p.Ala725Thr	missense_variant	Exon 15 of 18	1		ENSP00000393132.2	C9JWU6
LDB3	ENST00000263066.11 link	c.321+1621G>A		intron_variant	Intron 4 of 8	1	NM_001368067.1	ENSP00000263066.7	O75112-6

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000764

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000351

AC:

AN:

239460

AF XY:

0.000371

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000713

Gnomad OTH exome

AF:

0.000348

GnomAD4 exome

AF:

0.000381

AC:

551

AN:

1446538

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

277

AN XY:

717838

show subpopulations

African (AFR)

AF:

0.0000608

AC:

AN:

32920

American (AMR)

AF:

0.00

AC:

AN:

42744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25280

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83764

European-Finnish (FIN)

AF:

0.0000764

AC:

AN:

52344

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.000481

AC:

531

AN:

1104634

Other (OTH)

AF:

0.000201

AC:

AN:

59656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000348

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41592

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000764

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000712

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000387

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDB3: BP4, BS2 -

Jun 01, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified independently and in conjunction with additional variants in individuals with various cardiac phenotypes in published literature and tested at GeneDx; however, segregation data are limited at this time and this variant was also identified in control populations (Semmler et al., 2014; Lopes et al., 2015; Miszalski-Jamka et al., 2017); In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 25208129, 28798025, 25617006) -

Nov 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDB3 c.664G>A; p.Ala222Thr variant (rs139922045) is reported in the literature in individuals affected with hypertrophic cardiomyopathy, left ventricular noncompaction, myofibrillar myopathy, or inclusion body sinusitis, although it was not demonstrated to cause disease in these individuals (Lopes 2015, Miszalski-Jamka 2017, Semmler 2014, Weihl 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.07% (93/124816 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 45551). The alanine at codon 222 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Given the lack of clinical and functional data, the significance of the p.Ala222Thr 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. Miszalski-Jamka K et al. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2017 Aug;10(4). Semmler AL et al. Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies. Orphanet J Rare Dis. 2014 Aug 1;9:121. Weihl CC et al. Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis. Neuromuscul Disord. 2015 Apr;25(4):289-96. -

not specified

Uncertain:1Benign:1

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDB3 c.664G>A (p.Ala222Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 239460 control chromosomes, predominantly at a frequency of 0.00071 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 28.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05). c.664G>A has been reported in the literature in individuals affected with sporadic inclusion body myositis, myofibrillar myopathy, left ventricular non-compaction, and pediatric primary cardiomyopathy; in three cases a pathogenic variant in a different gene was reported in the patients which could explain their phenotype, supporting a benign role for LDB3 c.664G>A (Weihl_2015, Semmler_2014, Miszalski-Jamka_2017, Kuhnisch_2019, Kovacs_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37579221, 31568572, 28798025, 25208129, 25617006). ClinVar contains an entry for this variant (Variation ID: 45551). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 22, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Ala222Thr varia nt in LDB3 has been identified by our laboratory in 1 Caucasian infant with HCM, 1 Caucasian young adult with unspecified cardiomyopathy, and 1 Caucasian adult with HCM. This variant has also been identified in 4/8600 of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs139922045). Computational prediction tools do not provide strong su pport for or against an impact to the protein. However, alanine (Ala) at positio n 222 is not conserved in evolution and the change to threonine (Thr) is present in several species (black flying fox, megabat, and lizard), suggesting that a c hange at this position may be tolerated. In summary, while the clinical signific ance of the Ala222Thr variant is uncertain, these data suggest that it is more l ikely to be benign. -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Jun 25, 2019

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

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LDB3-related disorder

Benign:1

Feb 28, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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 23, 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

0.071

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;T;T;.;.

Eigen

Benign

0.026

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;.;T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.057

T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.1

M;M;M;.;M;M

PhyloP100

2.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

N;.;N;N;.;N

REVEL

Benign

0.095

Sift

Benign

0.24

T;.;T;D;.;D

Sift4G

Benign

0.37

T;T;T;T;T;T

Polyphen

0.0010, 0.19, 0.83

.;.;B;.;B;P

Vest4

0.24

MVP

0.72

MPC

0.20

ClinPred

0.068

GERP RS

3.7

Varity_R

0.11

gMVP

0.61

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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