rs763908636

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_StrongBS1_Supporting

The NM_007078.3(LDB3):c.1676G>A(p.Arg559Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,604,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R559W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 9.77

Publications

3 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 3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000657 (10/152198) while in subpopulation AFR AF = 0.000145 (6/41458). AF 95% confidence interval is 0.0000628. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.1676G>A	p.Arg559Gln	missense_variant, splice_region_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.1676G>A	p.Arg559Gln	missense_variant, splice_region_variant	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3		O75112-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000956

GnomAD2 exomes

AF:

0.0000218

AC:

AN:

229532

AF XY:

0.00000803

show subpopulations

Gnomad AFR exome

AF:

0.000278

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1452396

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

721904

show subpopulations

African (AFR)

AF:

0.000271

AC:

AN:

33200

American (AMR)

AF:

0.0000232

AC:

AN:

43120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39160

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52124

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1108002

Other (OTH)

AF:

0.0000833

AC:

AN:

60050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.0000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41458

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000109

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1C

Uncertain:1

Nov 04, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Uncertain:1

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Uncertain:1

Nov 25, 2015

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myofibrillar myopathy 4

Uncertain:1

Mar 18, 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_007078.3, and corresponds to NM_001080116.1:c.*17397G>A in the primary transcript. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 559 of the LDB3 protein (p.Arg559Gln). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is present in population databases (rs763908636, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden unexpected death in infancy (PMID: 26350513). ClinVar contains an entry for this variant (Variation ID: 464285). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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

Mar 17, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apparently de novo variant (denoted as c.1691G>A (R564Q) due to the use of a different alternate transcript) in a patient with sudden infant death syndrome (SIDS) (Hertz et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26350513) -

Cardiovascular phenotype

Uncertain:1

May 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R559Q variant (also known as c.1676G>A), located in coding exon 9 of the LDB3 gene, results from a G to A substitution at nucleotide position 1676. The amino acid change results in arginine to glutamine at codon 559, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. This variant was reported (as NM_001171610.1:c.1691G>A) in a sudden infant death case; however, clinical details were limited and has been reported in a cardiomyopathy cohort (Hertz CL et al. Eur. J. Hum. Genet., 2016 06;24:817-22; Akinrinade O et al. J Cardiovasc Transl Res, 2023 Dec;16:1287-1302). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

.;.;D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;.;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

2.0

.;.;M;.

PhyloP100

9.8

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0, 1.0

.;.;D;D

Vest4

0.84

MVP

0.94

MPC

0.81

ClinPred

0.81

GERP RS

4.8

Varity_R

0.54

gMVP

0.37

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.49

Position offset: 0

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