Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001046325 | SCV001210222 | uncertain significance | not provided | 2023-09-09 | criteria provided, single submitter | clinical testing | 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 variant disrupts the p.Thr409 amino acid residue in LRP5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18602879). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced 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 at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 843651). This variant has not been reported in the literature in individuals affected with LRP5-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 409 of the LRP5 protein (p.Thr409Met). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001844264 | SCV002103668 | uncertain significance | not specified | 2022-02-16 | criteria provided, single submitter | clinical testing | Variant summary: LRP5 c.1226C>T (p.Thr409Met) 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 0.00013 in 251178 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP5 causing Familial Exudative Vitreoretinopathy phenotype (6.3e-05), however the NGS technology used by gnomad cannot distinguish between the gene and other highly homologous regions of the genome, therefore this data should be taken with caution. To our knowledge, no occurrence of c.1226C>T in individuals affected with Familial Exudative Vitreoretinopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS. |
| Fulgent Genetics, |
RCV005004997 | SCV002796991 | 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 | 2024-05-15 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001046325 | SCV005331795 | uncertain significance | not provided | 2023-09-21 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |