rs199811186
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_007078.3(LDB3):c.845C>T(p.Thr282Met) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T282T) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
LDB3
NM_007078.3 missense
NM_007078.3 missense
Scores
9
7
1
Clinical Significance
Conservation
PhyloP100: 6.16
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAdExome4 at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDB3 | NM_007078.3 | c.845C>T | p.Thr282Met | missense_variant | 6/14 | ENST00000361373.9 | |
LDB3 | NM_001368067.1 | c.704C>T | p.Thr235Met | missense_variant | 7/9 | ENST00000263066.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.845C>T | p.Thr282Met | missense_variant | 6/14 | 1 | NM_007078.3 | P4 | |
LDB3 | ENST00000263066.11 | c.704C>T | p.Thr235Met | missense_variant | 7/9 | 1 | NM_001368067.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251072Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135736
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461736Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727158
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 25, 2015 | The p.Thr282Met variant in LDB3 has been identified by our laboratory in 1 adult with DCM and atrial fibrillation, who also carried a likely pathogenic variant in a different gene. This variant has been identified in 2/10330 African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199811186). Computational prediction tools and conservation analysis sug gest that this variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, the clinical significanc e of the p.Thr282Met variant is uncertain. - |
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 235 of the LDB3 protein (p.Thr235Met). This variant is present in population databases (rs199811186, gnomAD 0.01%). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 32183154). This variant is also known as c.845C>T, p.Thr282Met. ClinVar contains an entry for this variant (Variation ID: 179020). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2021 | Previously reported as T282M in a patient with left ventricular noncompaction in published literature (Hirono et al., 2020); Not observed at a significant frequency in large population cohorts (Lek 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: 32183154) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;D;.;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at