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

gnomAD frequency: 0.00036  dbSNP: rs139922045

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 4	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617985	SCV000736714	likely benign	Cardiovascular phenotype	2022-05-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000763673	SCV000894553	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000767125	SCV001150613	uncertain significance	not provided	2017-09-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767125	SCV001474642	uncertain significance	not 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798121	SCV002043385	likely benign	Cardiomyopathy	2019-06-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038764	SCV002511766	likely benign	not specified	2022-04-25	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.664G>A (p.Ala222Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 239460 control chromosomes, predominantly at a frequency of 0.00071 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 28.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.664G>A has been reported in the literature in individuals affected with sporadic inclusion body myositis, myofibrillar myopathy, left ventricular non-compaction, and pediatric primary cardiomyopathy; in the latter three cases a pathogenic variant in a different gene was reported in the patients which could explain their phenotype, supporting a benign role for LDB3 c.664G>A (Weihl_2015, Semmler_2014, Miszalski-Jamka_2017, Kuhnisch_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: four submitters classified the variant as VUS while three classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003934931	SCV004751117	likely benign	LDB3-related disorder	2022-02-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).