Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001306898 | SCV001496285 | likely pathogenic | not provided | 2024-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 444 of the LRP5 protein (p.Arg444His). This variant is present in population databases (rs761049544, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with LRP5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1009413). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRP5 protein function. This variant disrupts the p.Arg444 amino acid residue in LRP5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15981244, 17955262, 26244290; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004800970 | SCV005422917 | uncertain significance | not specified | 2024-10-08 | criteria provided, single submitter | clinical testing | Variant summary: LRP5 c.1331G>A (p.Arg444His) results in a non-conservative amino acid change in 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 2e-05 in 250148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1331G>A has been reported in the literature in a cohort of individuals affected with Familial Exudative Vitreoretinopathy, however no genotype-specific information was provided (Chen_2018, variant confirmed by personal communication as per HGMD database). This report does not provide unequivocal conclusions about association of the variant with Familial Exudative Vitreoretinopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30513533, 35885997). ClinVar contains an entry for this variant (Variation ID: 1009413). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Fulgent Genetics, |
RCV005050325 | SCV005684345 | uncertain significance | Bone mineral density quantitative trait locus 1; Exudative vitreoretinopathy 4; Worth disease; Autosomal dominant osteopetrosis 1; Osteoporosis with pseudoglioma; Polycystic liver disease 4 with or without kidney cysts | 2024-04-17 | criteria provided, single submitter | clinical testing |