ClinVar Miner

Submissions for variant NM_002335.4(LRP5):c.1300G>A (p.Asp434Asn)

gnomAD frequency: 0.00001  dbSNP: rs757888034
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001225923 SCV001398217 pathogenic not provided 2022-09-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LRP5 function (PMID: 16252235). 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) performed at Invitae indicates that this missense variant is expected to disrupt LRP5 protein function. ClinVar contains an entry for this variant (Variation ID: 953606). This missense change has been observed in individuals with clinical features of the autosomal recessive diseases exudative vitreoretinopathy and osteoporosis-pseudoglioma syndrome (PMID: 16252235, 28192794). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757888034, gnomAD 0.006%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 434 of the LRP5 protein (p.Asp434Asn).
GeneDx RCV001225923 SCV005420120 uncertain significance not provided 2024-05-29 criteria provided, single submitter clinical testing Observed in apparent homozygous state in a patient with nonsyndromic congenital retinal nonattachment in the literature and not observed in homozygous state in controls (PMID: 28192794); Published functional studies demonstrate reduced Wnt and Norrin signaling, but the significance of the reduced signaling cannot be determined (PMID: 16252235); 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: 16252235, 20340138, 28192794)
Fulgent Genetics, Fulgent Genetics RCV005050294 SCV005684341 likely pathogenic 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 2024-05-11 criteria provided, single submitter clinical testing

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