ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.668C>T (p.Ser223Leu) (rs375306400)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000223528 SCV000270354 likely benign not specified 2015-04-18 criteria provided, single submitter clinical testing p.Ser223Leu in exon 4 of LDB3: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 4 mammals (bushbaby, Chinese tree shrew, chinchilla and cape golden mole) ha ve a leucine (Leu) at this position despite high nearby amino acid conservation. In addition, it has been identified in 1/64126 European chromosomes, 2/9826 Afr ican chromosomes, and 1/12228 South Asian chromosomes by the Exome Aggregation C onsortium (ExAC,; dbSNP rs375306400).
Invitae RCV000456654 SCV000545677 uncertain significance Myofibrillar myopathy, ZASP-related 2017-07-06 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 223 of the LDB3 protein (p.Ser223Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. The LDB3 gene has multiple clinically relevant isoforms. The p.Ser223Leu variant occurs in alternate transcript NM_001171610.1, which corresponds to position c.321+1625C>T in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs375306400, ExAC 0.02%) but has not been reported in the literature in individuals with a LDB3-related disease. ClinVar contains an entry for this variant (Variation ID: 227498). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; Align-GVGD: "Class C0"). The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000766978 SCV000619694 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LDB3 gene. The S223L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/233922 (0.003%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The S223L 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, the S223L variant occurs in an alternate transcript where no definitively pathogenic variants have been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

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