Submissions for variant NM_002335.4(LRP5):c.3403C>T (p.Arg1135Cys)

gnomAD frequency: 0.00032  dbSNP: rs143396225

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000658613	SCV000226267	uncertain significance	not provided	2014-11-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658613	SCV000780391	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	LRP5: PP3, BS1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658613	SCV001375383	uncertain significance	not provided	2025-01-13	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 1135 of the LRP5 protein (p.Arg1135Cys). This variant is present in population databases (rs143396225, gnomAD 0.04%). This missense change has been observed in individual(s) with familial exudative vitreoretinopathy (PMID: 25711638). ClinVar contains an entry for this variant (Variation ID: 183256). 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. 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.
GeneDx	RCV000658613	SCV001986186	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	Observed in a patient with idiopathic low bone mass in published literature (PMID: 34639175); Observed in a patient with Familial Exudative Vitreoretinopathy (FEVR) in published literature (PMID: 25711638); Observed in unrelated patients with renal cysts in published literature (PMID: 25920554, 30652979); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30652979, 25920554, 28973524, 34426522, 25711638, 34639175)
Fulgent Genetics, Fulgent Genetics	RCV005003511	SCV002790092	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	2024-06-15	criteria provided, single submitter	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV000162090	SCV000212089	not provided	Polycystic kidney disease, adult type		no assertion provided	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000658613	SCV001798924	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658613	SCV001968958	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150959	SCV003839686	uncertain significance	not specified	2022-08-23	no assertion criteria provided	clinical testing	DNA sequence analysis of the LRP5 gene demonstrated a sequence change, c.3403C>T, in exon 15 that results in an amino acid change, p.Arg1135Cys. This sequence change has been previously described in an individual with two renal cysts (PMID: 25920554) and was also identified in a cohort of familial exudative vitreoretinopathy patients (PMID: 25711638). This sequence change has been described in the gnomAD database with a frequency of 0.025% in the overall population (dbSNP rs143396225). The p.Arg1135Cys change affects a highly conserved amino acid residue located in a domain of the LRP5 protein that is known to be functional. The p.Arg1135Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg1135Cys change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV003398827	SCV004103021	uncertain significance	LRP5-related disorder	2024-08-27	no assertion criteria provided	clinical testing	The LRP5 c.3403C>T variant is predicted to result in the amino acid substitution p.Arg1135Cys. This variant has been reported in an individual with familial exudative vitreoretinopathy (Patient 14471001 in Salvo et al. 2015. PubMed ID: 25711638), in a patient with autosomal dominant polycystic kidney disease (Cnossen et al. 2015. PubMed ID: 25920554), and in a patient with impaired bone mass and a family history of osteoporosis (Patient 12141 in Santa Rocca et al. 2021. PubMed ID: 34639175). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, an alternate missense change affecting the same amino acid (p.Arg1135His) has been reported in a patient with craniosynostosis (Patient 95463 in Clarke et al. 2018. PubMed ID: 29168297). Although we suspect that the c.3403C>T (p.Arg1135Cys) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.