chr10-86681769-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_007078.3(LDB3):​c.655C>T​(p.Arg219*) 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

2
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
BS2
High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDB3NM_007078.3 linkc.655C>T p.Arg219* stop_gained Exon 5 of 14 ENST00000361373.9 NP_009009.1 O75112-1
LDB3NM_001368067.1 linkc.321+1612C>T intron_variant Intron 4 of 8 ENST00000263066.11 NP_001354996.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDB3ENST00000361373.9 linkc.655C>T p.Arg219* stop_gained Exon 5 of 14 1 NM_007078.3 ENSP00000355296.3 O75112-1
ENSG00000289258ENST00000443292.2 linkc.2164C>T p.Arg722* stop_gained Exon 15 of 18 1 ENSP00000393132.2 C9JWU6
LDB3ENST00000263066.11 linkc.321+1612C>T intron_variant Intron 4 of 8 1 NM_001368067.1 ENSP00000263066.7 O75112-6

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152212
Hom.:
0
Cov.:
34
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:
9
AN:
241230
Hom.:
0
AF XY:
0.0000383
AC XY:
5
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:
38
AN:
1447906
Hom.:
0
Cov.:
32
AF XY:
0.0000223
AC XY:
16
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:
3
AN:
152212
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
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.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 21, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:2
Apr 16, 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 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. -

Oct 17, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Nov 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
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.321+1612C>T in the primary transcript. 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). This variant is present in population databases (rs727503123, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 163829). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1C Uncertain:1
Nov 30, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1
Sep 22, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.94
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.

Other links and lift over

dbSNP: rs727503123; hg19: chr10-88441526; COSMIC: COSV99555211; API