Submissions for variant NM_007078.3(LDB3):c.529dup (p.Ala177fs)

dbSNP: rs730880345

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155425	SCV000205115	uncertain significance	not specified	2012-11-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Ala177fs va riant in LDB3 has not been reported in the literature nor previously identified by our laboratory. This frameshift variant is predicted to alter the protein?s a mino acid sequence beginning at position 177 and lead to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein (loss of function). Studies in mice have shown that the spectrum of phenotypes resulting from homozygous loss of function of LDB3 i ncludes dilated cardiomyopathy (Zheng 2009; heart specific loss of function) and congenital myopathy (Zhou 2001, complete loss of function). However, loss-of-f unction variants have not yet been reported in individuals with cardio/myopathy and additional data is therefore needed to determine if the Ala177fs variant is disease causing.
GeneDx	RCV000767124	SCV000236015	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Reported using an alternate transcript of the gene
Invitae	RCV000469597	SCV000545690	uncertain significance	Myofibrillar myopathy 4	2016-09-13	criteria provided, single submitter	clinical testing	The frequency data for this variant (rs748794499) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a LDB3-related disease. ClinVar contains an entry for this variant (Variation ID: 178668). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in LDB3 cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance. This sequence change creates a frameshift at codon 177 (p.Ala177Glyfs*20) of the LDB3 gene. It is expected to result in an absent or disrupted protein product. The LDB3 gene has multiple clinically relevant isoforms. The p.Ala177Glyfs*20 variant occurs in alternate transcript NM_001171610.1, which corresponds to position c.321+1486dupG, in NM_001080116.1, the primary transcript listed in the Methods.
Ambry Genetics	RCV002345505	SCV002647182	uncertain significance	Cardiovascular phenotype	2020-12-18	criteria provided, single submitter	clinical testing	The c.529dupG variant, located in coding exon 4 of the LDB3 gene, results from a duplication of G at nucleotide position 529, causing a translational frameshift with a predicted alternate stop codon (p.A177Gfs*20). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of LDB3 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.