Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001238748 | SCV001411576 | likely pathogenic | not provided | 2024-02-20 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 507 of the LRP5 protein (p.Gly507Ser). This variant is present in population databases (rs765290711, gnomAD 0.003%). This missense change has been observed in individuals with osteoporosis-pseudoglioma syndrome (PMID: 22456437, 24423337). ClinVar contains an entry for this variant (Variation ID: 964514). 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. This variant disrupts the p.Gly507 amino acid residue in LRP5. Other variant(s) that disrupt this residue have been observed in individuals with LRP5-related conditions (PMID: 22456437; Invitae), which suggests that this may be a clinically significant amino acid residue. 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, |
RCV002222683 | SCV002500780 | uncertain significance | not specified | 2022-03-30 | criteria provided, single submitter | clinical testing | Variant summary: LRP5 c.1519G>A (p.Gly507Ser) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) 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 8e-06 in 251384 control chromosomes (gnomAD). c.1519G>A has been reported in the literature in individuals affected with Osteoporosis-Pseudoglioma Syndrome (Tuysuz_2012, Campos-Obando_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Fulgent Genetics, |
RCV002484301 | SCV002788522 | uncertain significance | Bone mineral density quantitative trait locus 1; Exudative vitreoretinopathy 4; Exudative vitreoretinopathy 1; Worth disease; Autosomal dominant osteopetrosis 1; Osteoporosis with pseudoglioma; Osteoporosis; Polycystic liver disease 4 with or without kidney cysts | 2021-12-30 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV003983855 | SCV004800203 | likely pathogenic | LRP5-related disorder | 2024-02-24 | no assertion criteria provided | clinical testing | The LRP5 c.1519G>A variant is predicted to result in the amino acid substitution p.Gly507Ser. This variant in the homozygous and compound heterozygous states were reported in two individuals with osteoporosis-pseudoglioma syndrome (Tuysuz et al 2012. PubMed ID: 22456437; Campos-Obando et al. 2014. PubMed ID: 24423337). In addition, a similar variant affecting the same amino acid (p.Gly507Arg) was reported in one individual with idiopathic osteoporosis (Table 3, Cohen et al. 2022. PubMed ID: 34743040). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. |