ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.664G>A (p.Ala222Thr) (rs139922045)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038764 SCV000062442 uncertain significance not specified 2014-04-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ala222Thr varia nt in LDB3 has been identified by our laboratory in 1 Caucasian infant with HCM, 1 Caucasian young adult with unspecified cardiomyopathy, and 1 Caucasian adult with HCM. This variant has also been identified in 4/8600 of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs139922045). Computational prediction tools do not provide strong su pport for or against an impact to the protein. However, alanine (Ala) at positio n 222 is not conserved in evolution and the change to threonine (Thr) is present in several species (black flying fox, megabat, and lizard), suggesting that a c hange at this position may be tolerated. In summary, while the clinical signific ance of the Ala222Thr variant is uncertain, these data suggest that it is more l ikely to be benign.
GeneDx RCV000767125 SCV000235992 likely benign not provided 2020-06-01 criteria provided, single submitter clinical testing Identified independently and in conjunction with additional variants in individuals with various cardiac phenotypes in published literature and tested at GeneDx; however, segregation data are limited at this time and this variant was also identified in control populations (Semmler et al., 2014; Lopes et al., 2015; Miszalski-Jamka et al., 2017); In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 25208129, 28798025, 25617006)
Invitae RCV001079636 SCV000638671 likely benign Myofibrillar myopathy, ZASP-related 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617985 SCV000736714 uncertain significance Cardiovascular phenotype 2020-03-24 criteria provided, single submitter clinical testing The p.A222T variant (also known as c.664G>A), located in coding exon 4 of the LDB3 gene, results from a G to A substitution at nucleotide position 664. The alanine at codon 222 is replaced by threonine, an amino acid with similar properties. This variant has been reported in an individual with sporadic inclusion body myositis, in subjects with hypertrophic cardiomyopathy (HCM), and in an individual with left ventricular non-compaction who also had a TTN variant; however, clinical details were limited for these individuals (Weihl CC et al. Neuromuscul. Disord., 2015 Apr;25:289-96; Lopes LR et al. Heart, 2015 Feb;101:294-301; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; Kühnisch J et al. Clin. Genet., 2019 Dec;96:549-559). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.036% (97/266014) total alleles studied. The highest observed frequency was 0.074% (91/122516) of non-Finnish European alleles.This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other 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 alteration remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000763673 SCV000894553 uncertain significance Dilated cardiomyopathy 1C; Myofibrillar myopathy, ZASP-related 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000767125 SCV001150613 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287897 SCV001474642 uncertain significance none provided 2019-11-08 criteria provided, single submitter clinical testing The LDB3 c.664G>A; p.Ala222Thr variant (rs139922045) is reported in the literature in individuals affected with hypertrophic cardiomyopathy, left ventricular noncompaction, myofibrillar myopathy, or inclusion body sinusitis, although it was not demonstrated to cause disease in these individuals (Lopes 2015, Miszalski-Jamka 2017, Semmler 2014, Weihl 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.07% (93/124816 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 45551). The alanine at codon 222 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Given the lack of clinical and functional data, the significance of the p.Ala222Thr variant is uncertain at this time. References: Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Miszalski-Jamka K et al. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2017 Aug;10(4). Semmler AL et al. Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies. Orphanet J Rare Dis. 2014 Aug 1;9:121. Weihl CC et al. Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis. Neuromuscul Disord. 2015 Apr;25(4):289-96.

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