ClinVar Miner

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

gnomAD frequency: 0.00005  dbSNP: rs375306400
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; dbSNP rs375306400).
Invitae RCV000456654 SCV000545677 uncertain significance Myofibrillar myopathy 4 2023-12-19 criteria provided, single submitter clinical testing The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.321+1625C>T in the primary transcript. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 223 of the LDB3 protein (p.Ser223Leu). This variant is present in population databases (rs375306400, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. 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: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. 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.
Ambry Genetics RCV002363062 SCV002663540 uncertain significance Cardiovascular phenotype 2022-10-27 criteria provided, single submitter clinical testing The p.S223L variant (also known as c.668C>T), located in coding exon 4 of the LDB3 gene, results from a C to T substitution at nucleotide position 668. The serine at codon 223 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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