ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1049C>T (p.Thr350Ile)

gnomAD frequency: 0.00022  dbSNP: rs200796750
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208120 SCV000264000 likely benign not specified 2015-10-19 criteria provided, single submitter clinical testing
Invitae RCV000229093 SCV000289613 uncertain significance Myofibrillar myopathy 4 2021-09-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 350 of the LDB3 protein (p.Thr350Ile). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*7309C>T in the primary transcript. This variant is present in population databases (rs200796750, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with Barth syndrome (PMID: 17394203). 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.
Mendelics RCV000229093 SCV001138107 benign Myofibrillar myopathy 4 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV001580470 SCV001817573 uncertain significance not provided 2019-03-14 criteria provided, single submitter clinical testing Reported in the literature in a patient with Barth syndrome and severe LVNC/DCM, and was also identified in this patient's sibling and father, who have prominent trabeculations but do not meet criteria for LVNC (Marziliano et al., 2007; Arbustini et al., 2016); this patient also harbors a maternally inherited frameshift variant in the TAZ gene; Reported also in association with HCM (Lopes et al., 2015); Identified both independently and in conjunction with additional cardiogenetic variants in unrelated individuals with DCM referred for genetic testing at GeneDx, but segregation data is limited or absent at this time; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 222687; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25351510, 17394203, 27561770, 23299917, 21303826)
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254737 SCV001430819 likely benign Hypertrophic cardiomyopathy 2019-11-26 no assertion criteria provided research LDB3 Thr350Ile has been reported previously in 1 proband diagnosed with Barth Syndrome and left ventricular noncompaction, he was also found to be hemizygous for the TAZ Glu202Valfs variant (Marziliano N, et al., 2007). We identified this variant in a HCM proband of Eastern European descent and no family history of HCM or sudden cardiac death. The variant is present in the Genome Aggregation Database (MAF= 0.00013, http://gnomad.broadinstitute.org/), at an allele frequency which higher than expected for these disorders. Computational tools SIFT and PolyPhen2 predict this variant to have a deleterious effect, however MutationTaster predicts this variant to be a "polymorphism". In summary, based on the elevated allele frequency in the general population and limited information we classify LDB3 Thr350Ile as a variant of "uncertain significance".

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