Submissions for variant NM_002335.4(LRP5):c.3245A>G (p.Tyr1082Cys)

gnomAD frequency: 0.00011  dbSNP: rs113804402

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000658612	SCV000780390	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000658612	SCV001999752	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	Reported with a second variant on the opposite allele (in trans) in a patient with FEVR in published literature (Tao et al., 2021); Reported in the heterozygous state in multiple individuals belonging to a single family with early-onset osteoporosis in published literature (Sturznickel et al., 2020); 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: 34860240, 33118644)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658612	SCV002264344	pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1082 of the LRP5 protein (p.Tyr1082Cys). This variant is present in population databases (rs113804402, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive exudative vitreoretinopathy (PMID: 34860240; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 546679). 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) indicates that this missense variant is expected to disrupt LRP5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317323	SCV004020872	uncertain significance	not specified	2023-06-08	criteria provided, single submitter	clinical testing	Variant summary: LRP5 c.3245A>G (p.Tyr1082Cys) results in a non-conservative amino acid change in 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-05 in 249336 control chromosomes (gnomAD), predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP5 causing Familial Exudative Vitreoretinopathy (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3245A>G has been reported in the literature in heterozygous individuals affected with Early-onset osteoporosis (Sturznickel_2021) and in a compound heterozygous individual with Exudative Vitreoretinopathy with unaffected heterozygous parents (Tao_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Exudative Vitreoretinopathy. 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: 33118644, 34860240). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005049632	SCV005684856	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	2024-02-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742559	SCV005353292	uncertain significance	LRP5-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The LRP5 c.3245A>G variant is predicted to result in the amino acid substitution p.Tyr1082Cys. This variant was reported in an individual with Osteoporosis, early-onset (Stürznickel et al. 2021. PubMed ID: 33118644; Tao et al. 2021. PubMed ID: 34860240). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this 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.