rs727503123
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
Consequence
NM_007078.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDB3 | NM_007078.3 | c.655C>T | p.Arg219Ter | stop_gained | 5/14 | ENST00000361373.9 | |
LDB3 | NM_001368067.1 | c.321+1612C>T | intron_variant | ENST00000263066.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.655C>T | p.Arg219Ter | stop_gained | 5/14 | 1 | NM_007078.3 | P4 | |
LDB3 | ENST00000263066.11 | c.321+1612C>T | intron_variant | 1 | NM_001368067.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000373 AC: 9AN: 241230Hom.: 0 AF XY: 0.0000383 AC XY: 5AN XY: 130408
GnomAD4 exome AF: 0.0000262 AC: 38AN: 1447906Hom.: 0 Cov.: 32 AF XY: 0.0000223 AC XY: 16AN XY: 718392
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74352
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at