ClinVar Genomic variation as it relates to human health

p.Arg31Trp (R31W) CGG>TGG: c.91 C>T in exon 1 of the LDB3 gene (NM_007078.2). The R31W variant in the LDB3 gene has not been published as a disease-causing mutation or a benign polymorphism to our knowledge. The R31W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R31W 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. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function (Adzhubei I et al., 2010; Schwarz J et al., 2011). Nevertheless, no missense mutations in nearby residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM panel(s).

Variant summary: LDB3 c.91C>T (p.Arg31Trp) results in a non-conservative amino acid change located in the PDZ domain (IPR001478) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249228 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.91C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change results in a missense variant in the LDB3 gene (p.(Arg31Trp)). This variant is present in population databases with a prevalence of 12/244674 in GnomAD. This variant has not been reported in the literature and no functional data are available. Prediction programs predict the variant to be pathogenic ( Align GVGD: pathogenic, C65; Polyphen-2-HumDiv probably damaging; Polyphen-2-HumVar probably damaging; SIFT deleterious, MutationTaster: disease causing; PP3). The variant affects a low conserved nucleotide and a highly conserved amino acid. We identified this variant in 2 unrelated patients with HCM, A patients with DCM and a patient with possible ARVC. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: PP3).

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. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 31 of the LDB3 protein (p.Arg31Trp). This variant is present in population databases (rs367792378, gnomAD 0.03%). 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: 201857). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.

The p.R31W variant (also known as c.91C>T), located in coding exon 1 of the LDB3 gene, results from a C to T substitution at nucleotide position 91. The arginine at codon 31 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in cardiomyopathy cohorts; however, clinical details were limited and additional alterations in other cardiac-related genes were identified (Robyns T et al. Eur J Hum Genet, 2017 Dec;25:1313-1323; Boen HM et al. J Heart Lung Transplant, 2022 Sep;41:1218-1227). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.