Submissions for variant NM_007078.3(LDB3):c.529dup (p.Ala177fs) (rs730880345)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare 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	2014-02-27	criteria provided, single submitter	clinical testing	The c.529dupG variant in the LDB3 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.529dupG variant causes a shift in reading frame starting at codon Alanine 177, changing it to a Glycine, and creating a premature stop codon at position 20 of the new reading frame. This variant is expected to result either in an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, no variants associated with haploinsuffiency (e.g. nonsense, small insertions/deletions) have been reported in the LDB3 gene in association with cardiomyopathy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000469597	SCV000545690	uncertain significance	Myofibrillar myopathy, ZASP-related	2016-09-13	criteria provided, single submitter	clinical testing	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. 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.