Submissions for variant NM_007078.3(LDB3):c.1609del (p.Gln537fs)

dbSNP: rs727503129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150927	SCV000198569	uncertain significance	not specified	2013-10-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Gln537fs va riant in LDB3 has not been previously reported in any other families with cardio myopathy or in large European American or African American cohorts. This framesh ift variant is predicted to alter the protein?s amino acid sequence beginning at position 537 and lead to a premature termination codon 28 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein (l oss of function). Studies in mice have shown that the spectrum of phenotypes res ulting from homozygous loss of function of LDB3 includes DCM (Zheng 2009; heart specific loss of function) and congenital myopathy (Zhou 2001, complete loss of function). Our laboratory has previously identified one loss of function varian t in an individual with VT and SCA but overall, this type of variant has not yet been reported in individuals with cardio/myopathy. In summary, the predicted im pact to the protein increases the likelihood that this variant is pathogenic but additional studies are required to fully establish its clinical significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622367	SCV000740592	likely pathogenic	not provided	2016-06-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769290	SCV000900668	uncertain significance	Cardiomyopathy	2017-07-26	criteria provided, single submitter	clinical testing
Invitae	RCV001245723	SCV001419026	uncertain significance	Myofibrillar myopathy 4	2020-09-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln537Argfs*28) in the LDB3 gene. It is expected to result in an absent or disrupted protein product. The LDB3 gene has multiple clinically relevant transcripts. The p.Gln537Argfs*28 variant occurs in alternate transcript NM_007078.2, which corresponds to c.*17330del in NM_001080116.1, the primary transcript listed in the Methods. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 163850). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in LDB3 cause disease. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150927	SCV003801041	uncertain significance	not specified	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.1609delC (p.Gln537ArgfsX28) 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. The variant allele was found at a frequency of 2.7e-05 in 150748 control chromosomes (gnomAD v3.1). To our knowledge, no occurrence of c.1609delC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. In ClinVar, all nonsense or truncation variants are classified as uncertain significance, including truncations upstream and downstream of this position. Additionally, the LDB3 gene is classified as "limited association" with dilated cardiomyopathy and "disputed association" with arrhythmogenic right ventricular cardiomyopathy by ClinGen. Therefore, currently available evidence does not support that loss-of-function variants are pathogenic for Cardiomyopathy. Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (n=1), or VUS (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV003298157	SCV003992284	uncertain significance	Cardiovascular phenotype	2023-04-07	criteria provided, single submitter	clinical testing	The c.1609delC variant, located in coding exon 9 of the LDB3 gene, results from a deletion of one nucleotide at nucleotide position 1609, causing a translational frameshift with a predicted alternate stop codon (p.Q537Rfs*28). 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.