Submissions for variant NM_007078.3(LDB3):c.1823C>T (p.Pro608Leu)

gnomAD frequency: 0.00009  dbSNP: rs145983824

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038742	SCV000062420	uncertain significance	not specified	2014-02-17	criteria provided, single submitter	clinical testing	The Pro608Leu variant in LDB3 has now been identified by our laboratory in 1 Cau casian adult with LVNC and biventricular enlargement, who also carried a likely pathogenic variant in another gene, and 1 Black adult with DCM (LMM unpublished data; including this individual). In addition, this variant has also been identi fied in 1/8600 European American chromosomes and in 2/4406 African American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/ ; dbSNP rs145983824). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may imp act the protein, though this information is not predictive enough to determine p athogenicity. Additional information is needed to fully assess the clinical sign ificance of the Pro608Leu variant.
GeneDx	RCV000767179	SCV000536381	uncertain significance	not provided	2020-01-13	criteria provided, single submitter	clinical testing	Reported as P615L in an adult male with HCM (Theis et al., 2006); Reported in ClinVar (ClinVar Variant ID# 45533; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28518168, 17097056)
Invitae	RCV000558390	SCV000638690	uncertain significance	Myofibrillar myopathy 4	2023-12-10	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.*18736C>T in the primary transcript. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 608 of the LDB3 protein (p.Pro608Leu). This variant is present in population databases (rs145983824, gnomAD 0.009%). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767179	SCV002048917	uncertain significance	not provided	2021-01-20	criteria provided, single submitter	clinical testing	The LDB3 c.1823C>T; p.Pro608Leu variant (rs145983824), also known as c.*18736C>T for NM_001080116.1, is reported in the literature in an individual affected with hypertrophic cardiomyopathy (reported as Pro615Leu, Theis 2006). This variant is also reported in ClinVar (Variation ID: 45533), and is found in the general population with an overall allele frequency of 0.0074% (21/282888 alleles) in the Genome Aggregation Database. The proline at codon 608 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.759). However, given the lack of clinical and functional data, the significance of the p.Pro608Leu variant is uncertain at this time. References: Theis JL et al. Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2006 Dec 29;351(4):896-902.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038742	SCV002572239	uncertain significance	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.1823C>T (p.Pro608Leu) results in a non-conservative amino acid change located in the zinc finger, LIM-type domain (IPR001781) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251488 control chromosomes (gnomAD). The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant may be benign. c.1823C>T has been reported in the literature in settings of multigene panel testing in individuals affected with dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction (e.g. Theis_2006, Akinrinade_2015, Walsh_2017, Mazzarotto_2021, Shen_2022). These report(s) do not provide unequivocal conclusions about association of the variant with cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002408520	SCV002712068	uncertain significance	Cardiovascular phenotype	2022-01-26	criteria provided, single submitter	clinical testing	The p.P608L variant (also known as c.1823C>T), located in coding exon 10 of the LDB3 gene, results from a C to T substitution at nucleotide position 1823. The proline at codon 608 is replaced by leucine, an amino acid with similar properties. This variant (referred to as p.P615L) has been reported in an individual with hypertrophic cardiomyopathy (Theis JL et al. Biochem. Biophys. Res. Commun., 2006 Dec;351:896-902), and has also been reported in an exome cohort; however, clinical details were limited (Tang D et al. Sci Rep, 2018 Jul;8:10912). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002490528	SCV002779262	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2022-04-15	criteria provided, single submitter	clinical testing
OMIM	RCV000170304	SCV000222652	pathogenic	Familial hypertrophic cardiomyopathy 24	2006-12-29	no assertion criteria provided	literature only