ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.2092G>A (p.Ala698Thr)

gnomAD frequency: 0.00026  dbSNP: rs45577134
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Total submissions: 8
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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 RCV000038750 SCV000062428 uncertain significance not specified 2014-08-01 criteria provided, single submitter clinical testing The Ala698Thr variant in LDB3 has been reported in 2 individuals with DCM, both of whom also carry an additional variant in another cardiomyopathy-associated ge ne (Hershberger 2008, Li 2010). This variant has also been identified by our lab oratory in 1 Native American individual with HCM and 1 African American infant w ith DCM. This variant has been identified in 6/8600 European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs45577134). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, the clinical significance of the Ala698Thr variant is uncertain.
GeneDx RCV000767131 SCV000236011 likely benign not provided 2021-04-23 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19412328, 20590677, 22337857, 23299917, 25163546, 30547036)
Invitae RCV000463936 SCV000545672 uncertain significance Myofibrillar myopathy 4 2024-01-22 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.*26876G>A in the primary transcript. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 698 of the LDB3 protein (p.Ala698Thr). This variant is present in population databases (rs45577134, gnomAD 0.04%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19412328, 20590677, 25163546). This variant is also known as c.G1762A (p.A588T). ClinVar contains an entry for this variant (Variation ID: 36446). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Ambry Genetics RCV000617552 SCV000736138 uncertain significance Cardiovascular phenotype 2023-09-11 criteria provided, single submitter clinical testing The p.A698T variant (also known as c.2092G>A), located in coding exon 12 of the LDB3 gene, results from a G to A substitution at nucleotide position 2092. The alanine at codon 698 is replaced by threonine, an amino acid with similar properties. This alteration was reported in two unrelated probands with dilated cardiomyopathy (DCM); however, both carried variants in other DCM-associated genes (Hershberger RE et al. Clin Transl Sci. 2008;1:21-6; Li D et al. Clin Transl Sci. 2010;3:90-7). This alteration has also been detected in DCM and cardiomyopathy genetic testing cohorts (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been detected in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet. 2013;21:918-28). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770300 SCV000901733 uncertain significance Cardiomyopathy 2020-05-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000767131 SCV001159726 likely benign not provided 2023-10-31 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470722 SCV002767753 likely benign Dilated cardiomyopathy 1C 2020-10-19 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (67 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in the annotated LIM zinc-binding 3 domain. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Ala703Ser) has one VUS entry in ClinVar. (N) 0806 - Moderate previous evidence of neutrality in unrelated individuals. Identified in multiple patients at VCGS with LQTS and Brugada syndrome. This variant has six VUS and one likely benign entry in ClinVar. (B) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) – Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030118 SCV000052773 likely benign Primary dilated cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing

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