Submissions for variant NM_007078.3(LDB3):c.1253C>G (p.Pro418Arg)

gnomAD frequency: 0.00013  dbSNP: rs141870580

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463144	SCV000545689	uncertain significance	Myofibrillar myopathy 4	2023-12-25	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.*16974C>G in the primary transcript. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 418 of the LDB3 protein (p.Pro418Arg). This variant is present in population databases (rs141870580, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 406810). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000600447	SCV000710911	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	The p.Pro418Arg variant in LDB3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 14/65594 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s141870580). Computational prediction tools and conservation analysis suggest th at the p.Pro418Arg variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Pro418Arg variant is uncertain.
Ambry Genetics	RCV000621788	SCV000737217	uncertain significance	Cardiovascular phenotype	2022-06-24	criteria provided, single submitter	clinical testing	The p.P418R variant (also known as c.1253C>G), located in coding exon 9 of the LDB3 gene, results from a C to G substitution at nucleotide position 1253. The proline at codon 418 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in an individual referred for genetic testing for dilated cardiomyopathy (VanDyke RE et al. J Genet Couns. 2021 04;30(2):503-512). This amino acid position is highly 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622484	SCV000740598	uncertain significance	Primary familial dilated cardiomyopathy	2017-05-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001544779	SCV001763977	uncertain significance	not provided	2019-04-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 406810; Landrum et al., 2016)
Fulgent Genetics, Fulgent Genetics	RCV002480376	SCV002780752	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000600447	SCV004241148	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.1253C>G (p.Pro418Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 248242 control chromosomes. The observed variant frequency is approximately 3.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is could be benign, however, evidence is insufficient to draw any conclusions. To our knowledge, c.1253C>G has not been reported in the literature in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30021846). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.