Submissions for variant NM_007078.3(LDB3):c.550A>G (p.Lys184Glu)

gnomAD frequency: 0.00001  dbSNP: rs774886148

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767013	SCV000491832	uncertain significance	not provided	2017-06-02	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LDB3 gene. The K184E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K184E variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Though also not observed in these aforementioned populations by the Exome Aggregation Consortium (ExAc), ExAc did observe K184E in 10/11522 (0.09%) alleles from individuals of Latino background. The K184E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079727	SCV000638694	likely benign	Myofibrillar myopathy 4	2024-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619242	SCV000737247	benign	Cardiovascular phenotype	2024-05-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
New York Genome Center	RCV001836757	SCV002097661	uncertain significance	Dilated cardiomyopathy 1C	2020-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223723	SCV004122629	likely benign	not specified	2023-10-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767013	SCV005875349	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	The LDB3 c.550A>G; p.Lys184Glu variant (rs774886148), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 235003). This variant is observed in the general population with an overall allele frequency of 0.01% (33/280930 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.018). Due to limited information, the clinical significance of this variant is uncertain at this time.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223723	SCV000280178	uncertain significance	not specified	2015-02-17	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LDB3 p.Lys184Glu Based on the data reviewed below we consider this variant of unknown significance, probably benign. The p.K184E variant (also known as c.550A>G) is located in coding exon 4 of the LDB3 gene. The lysine at codon 184 is replaced by glutamic acid, an amino acid with some similar properties. A journal search did not elucidate any previous reports of this variant in association with disease. In silico analysis with PolyPhen-2 predicts the variant to be benign. The 184 at codon is not well conserved across vertebrate species. In total the variant has not been seen in ~6,500 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 184 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/27/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 7/25/13).
PreventionGenetics, part of Exact Sciences	RCV003967607	SCV004782143	likely benign	LDB3-related disorder	2023-11-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).