Submissions for variant NM_007078.3(LDB3):c.655C>T (p.Arg219Ter)

gnomAD frequency: 0.00001  dbSNP: rs727503123

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150918	SCV000198544	uncertain significance	not specified	2014-04-16	criteria provided, single submitter	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.
GeneDx	RCV000766441	SCV000680933	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	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)
Invitae	RCV001242445	SCV001415532	pathogenic	Myofibrillar myopathy 4	2023-08-17	criteria provided, single submitter	clinical testing	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.
Genetics and Molecular Pathology, SA Pathology	RCV002466447	SCV002761785	uncertain significance	Dilated cardiomyopathy 1C	2021-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150918	SCV004121754	uncertain significance	not specified	2023-10-17	criteria provided, single submitter	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.
Ambry Genetics	RCV004019809	SCV005025492	uncertain significance	Cardiovascular phenotype	2023-09-22	criteria provided, single submitter	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766441	SCV001958194	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766441	SCV001964623	uncertain significance	not provided		no assertion criteria provided	clinical testing