rs727503123

Positions:

chr10-86681769-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_007078.3(LDB3):c.655C>T(p.Arg219Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,600,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

LDB3
NM_007078.3 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.655C>T	p.Arg219Ter	stop_gained	5/14	ENST00000361373.9
LDB3	NM_001368067.1 linkuse as main transcript	c.321+1612C>T		intron_variant		ENST00000263066.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.655C>T	p.Arg219Ter	stop_gained	5/14	1	NM_007078.3	P4	O75112-1
LDB3	ENST00000263066.11 linkuse as main transcript	c.321+1612C>T		intron_variant		1	NM_001368067.1		O75112-6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000373

AC:

AN:

241230

Hom.:

AF XY:

0.0000383

AC XY:

AN XY:

130408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000606

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000354

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.0000455

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000262

AC:

AN:

1447906

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

718392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000463

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000299

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000389

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2023	In an abstract by Gotway et al., 2023, the p.(R219X) variant was identified in trans with a second nonsense variant in the LDB3 gene in two brothers with LVNC as newborns that improved over time; Identified in a control patient with hypertension-related cardiac hypertrophy (Holmstrom et al., 2021); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not an established mechanism of disease; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 34045587) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2014	Variant classified as Uncertain Significance - Favor Pathogenic. The Arg219X var iant in LDB3 has not been reported in individuals with cardiomyopathy or in larg e population studies. This nonsense variant leads to a premature termination cod on at position 219, which is predicted to lead to a truncated or absent protein (loss-of-function). Studies of mouse models support that absence of LDB3 in the heart leads to DCM (Zheng 2009); however, this has not been well studied in huma ns. Our laboratory has detected homozygous/compound heterozygous loss-of-functio n variants in LDB3 in 2 neonates with DCM +/- LVNC and 1 individual with VT and SCA carried heterozygous loss of function variant. These data suggest that loss- of-function variants in LDB3 are pathogenic in the homozygous/compound heterozyg ous state but additional studies are needed to fully establish their clinical si gnificance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2023	Variant summary: LDB3 c.655C>T (p.Arg219X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in LDB3 as causative of disease. The variant allele was found at a frequency of 3.7e-05 in 241230 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. An alternate transcript is also associated with this variant: NM_001080116 c.321+1612C>T. c.655C>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy and alcoholic cardiomyopathy, without evidence of causation (Ware_2018, Holmstrom_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. 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: 34045587, 34691145, 29773157). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Myofibrillar myopathy 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 163829). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. This variant is present in population databases (rs727503123, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg219*) in the LDB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDB3 are known to be pathogenic (PMID: 36253531). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.321+1612C>T in the primary transcript. -

Dilated cardiomyopathy 1C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Nov 30, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The p.R219* variant (also known as c.655C>T), located in coding exon 4 of the LDB3 gene, results from a C to T substitution at nucleotide position 655. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in a cardiomyopathy cohort and a sudden cardiac death cohort; however, clinical details were limited in both cases (Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; Holmström L et al. Sci Rep, 2021 May;11:11171). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of LDB3 has not been established as a mechanism of disease. 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

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;A;A;A;A;A;D;D;D;D

Vest4

0.89

GERP RS

2.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.21

Position offset: 34

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