Submissions for variant NM_002335.4(LRP5):c.98C>T (p.Pro33Leu)

gnomAD frequency: 0.00001  dbSNP: rs753259758

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000329117	SCV000329405	uncertain significance	not provided	2016-03-14	criteria provided, single submitter	clinical testing	The P33L variant in the LRP5 gene has not been published as a pathogenic variant, nor has it been reported as a benign substitution to our knowledge. The P33L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A missense variant in a nearby residue (A29T) has been reported in the Human Gene Mutation Database in association with LRP5-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. The P33L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P33L as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000329117	SCV001545615	uncertain significance	not provided	2023-05-31	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. 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: 279843). This variant has not been reported in the literature in individuals affected with LRP5-related conditions. This variant is present in population databases (rs753259758, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 33 of the LRP5 protein (p.Pro33Leu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479087	SCV004222678	uncertain significance	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: LRP5 c.98C>T (p.Pro33Leu) results in a non-conservative amino acid change in 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 4e-06 in 247466 control chromosomes. 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.98C>T in individuals affected with LRP5-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005049508	SCV005684280	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	2024-04-23	criteria provided, single submitter	clinical testing