ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.690-4661G>A (rs373632943)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150920 SCV000198549 uncertain significance not specified 2013-04-09 criteria provided, single submitter clinical testing The Ala171Thr variant in LDB3 has not been reported in the literature but has pr eviously been identified by our laboratory in 3 individuals of Ashkenazi Jewish ancestry (1 with HCM, 1 with DCM, and 1 with DCM and LVNC). This variant has be en identified in 2/8514 European American chromosomes by the NHLBI Exome Sequenc ing Project ( It is possible that this varian t is common in the Ashkenazi Jewish population but appropriate control cohorts w oudl need to be sequenced to determine this. Computational analyses (biochemica l amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not pr ovide strong support for or against an impact to the protein. Additional studie s are needed to fully assess the clinical significance of this variant.
GeneDx RCV000150920 SCV000490600 uncertain significance not specified 2016-09-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in an alternate transcript of the LDB3 gene. In vitro expression of A171T showed absent or decreased binding of the LDB3 protein to other sarcomeric proteins, and analysis of a different variant (A165V) in LDB3, previously reported in association with autosomal dominant distal myopathy, displayed a similar effect (Martinelli et al., 2014). A171T was not observed with any significant frequency in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This 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, and this substitution occurs at a position that is conserved across species. Although A171T has been identified independently and/or in conjunction with additional cardiogenetic variants in other individuals referred for cardiomyopathy genetic testing at GeneDx, observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the pathogenicity of this variant. Moreover, this variant was homozygous in one individual in the Exome Aggregation Consortium. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000467142 SCV000557537 likely benign Myofibrillar myopathy, ZASP-related 2020-11-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621927 SCV000736985 uncertain significance Cardiovascular phenotype 2016-04-08 criteria provided, single submitter clinical testing The p.A171T variant (also known as c.511G>A), located in coding exon 5 of the LDB3 gene, results from a G to A substitution at nucleotide position 511. The alanine at codon 171 is replaced by threonine, an amino acid with similar properties. In vitro studies suggested that this alteration might interfere with protein interactions(MartinelliVC et al.PLoS ONE.2014;9(3):e92259).This variant was previously reported in theSNPDatabaseasrs373632943.Based on data from ExAC, the A allele has an overall frequency of approximately 0.04% (44/105556).Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/12874) total alleles studied and 0.02% (2/8514) European American alleles. This amino acid position is highly conserved in available 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 variant remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000467142 SCV001259681 uncertain significance Myofibrillar myopathy, ZASP-related 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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