ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1049C>T (p.Thr350Ile) (rs200796750)

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Total submissions: 4
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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, ZASP-related 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 350 of the LDB3 protein (p.Thr350Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. The LDB3 gene has multiple clinically relevant isoforms. The p.Thr350Ile variant occurs in alternate transcript NM_007078.3, which corresponds to c.*7309C>T in NM_001080116.1, the primary transcript listed in the Methods. This variant is present in population databases (rs200796750, ExAC 0.02%). This variant has been reported in an individual affected Barth syndrome and in two unaffected relatives (PMID: 17394203). In addition, one pathogenic allele was identified in the TAZ gene in the reported patient, which suggests that this c.1049C>T substitution in LDB3 was not the primary cause of disease in this individual. ClinVar contains an entry for this variant (Variation ID: 222687). 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; PolyPhen-2: Not Available; Align-GVGD: Class C0). 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, ZASP-related 2019-05-28 criteria provided, single submitter clinical testing
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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