ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.550A>G (p.Lys184Glu) (rs774886148)

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Total submissions: 4
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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.
Invitae RCV000535341 SCV000638694 uncertain significance Myofibrillar myopathy, ZASP-related 2017-05-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 189 of the LDB3 protein (p.Lys184Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. The LDB3 gene has multiple clinically relevant isoforms. The p.Lys184Glu variant occurs in alternate transcript NM_001171610.1, which corresponds to position c.321+1507A>G in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs774886148, ExAC 0.09%) but has not been reported in the literature in individuals with a LDB3-related disease. ClinVar contains an entry for this variant (Variation ID: 235003). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619242 SCV000737247 uncertain significance Cardiovascular phenotype 2017-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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).

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