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

gnomAD frequency: 0.00022  dbSNP: rs200796750

Total submissions: 6

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	2024-01-04	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.*7309C>T in the primary transcript. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 350 of the LDB3 protein (p.Thr350Ile). This variant is present in population databases (rs200796750, gnomAD 0.03%). This missense change has been observed in individual(s) with Barth syndrome (PMID: 17394203). ClinVar contains an entry for this variant (Variation ID: 222687). 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)
Ambry Genetics	RCV002390557	SCV002703923	uncertain significance	Cardiovascular phenotype	2023-07-18	criteria provided, single submitter	clinical testing	The p.T350I variant (also known as c.1049C>T), located in coding exon 7 of the LDB3 gene, results from a C to T substitution at nucleotide position 1049. The threonine at codon 350 is replaced by isoleucine, an amino acid with similar properties. This variant co-occurred with a TAZ frameshift alteration in an individual with Barth syndrome and non-compaction cardiomyopathy. The proband's healthy father and brother had the LDB3 variant and showed prominent cardiac trabeculation, and otherwise normal cardiac exam (Marziliano N et al. Am. J. Med. Genet. A, 2007 May;143A:907-15). This alteration has also been reported in a limb girdle muscular dystrophy cohort (Marziliano N et al. Am. J. Med. Genet. A, 2007 May;143A:907-15). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28). This amino acid position is not conserved on limited sequence alignment. 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.
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".