rs147072071
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_007078.3(LDB3):āc.1487T>Cā(p.Phe496Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00011 ( 0 hom., cov: 31)
Exomes š: 0.00011 ( 0 hom. )
Consequence
LDB3
NM_007078.3 missense
NM_007078.3 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 5.89
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 GnomAd4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDB3 | NM_007078.3 | c.1487T>C | p.Phe496Ser | missense_variant | 10/14 | ENST00000361373.9 | NP_009009.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.1487T>C | p.Phe496Ser | missense_variant | 10/14 | 1 | NM_007078.3 | ENSP00000355296 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 151350Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000721 AC: 18AN: 249792Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135174
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GnomAD4 exome AF: 0.000112 AC: 164AN: 1461846Hom.: 0 Cov.: 36 AF XY: 0.000113 AC XY: 82AN XY: 727226
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GnomAD4 genome AF: 0.000112 AC: 17AN: 151350Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 11AN XY: 73890
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2024 | Reported using an alternate transcript of the gene; Identified in patients with sudden unexplained death and dilated cardiomyopathy in the published literature; described as Phe386Ser, Phe496Ser, and Phe501Ser using various alternate transcripts (PMID: 29247119, 30847666, 32746448, 33919104); 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: 33919104, 32746448, 30847666, 29247119) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 09, 2021 | - - |
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 18, 2023 | The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17208T>C in the primary transcript. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 496 of the LDB3 protein (p.Phe496Ser). This variant is present in population databases (rs147072071, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of LDB3-related conditions (PMID: 29247119, 30847666, 32746448). This variant is also known as c.180T>C (p.Phe386Ser). ClinVar contains an entry for this variant (Variation ID: 201849). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2024 | The p.F496S variant (also known as c.1487T>C), located in coding exon 9 of the LDB3 gene, results from a T to C substitution at nucleotide position 1487. The phenylalanine at codon 496 is replaced by serine, an amino acid with highly dissimilar properties. This variant (also described as p.F386S) has been reported in a sudden unexplained death case and a dilated cardiomyopathy genetic testing case; however, clinical details were limited for both individuals (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This alteration has also been reported in a pediatric cardiomyopathy cohort (Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;M;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D
REVEL
Benign
Sift
Benign
T;.;T;T
Sift4G
Uncertain
D;D;D;T
Polyphen
0.74, 0.89
.;.;P;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
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