Submissions for variant NM_002335.4(LRP5):c.796C>T (p.Arg266Cys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003062420	SCV003440556	uncertain significance	not provided	2024-07-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 266 of the LRP5 protein (p.Arg266Cys). This variant is present in population databases (rs368484557, gnomAD 0.008%). This missense change has been observed in individual(s) with high bone mass (PMID: 26348019, 31816670). ClinVar contains an entry for this variant (Variation ID: 2137175). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479464	SCV004222932	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: LRP5 c.796C>T (p.Arg266Cys) 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 3.2e-05 in 250504 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.796C>T has been reported in the literature in individuals affected with high bone density or retinal dystrophy without strong evidence of causality (Gregson_2016, Yohe_2020). These reports do not provide unequivocal conclusions about association of the variant with Endosteal Hyperostosis. 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: 26348019, 31816670). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005050705	SCV005684311	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	2024-03-04	criteria provided, single submitter	clinical testing