Submissions for variant NM_002335.4(LRP5):c.2737dup (p.Cys913fs)

gnomAD frequency: 0.00001  dbSNP: rs886043590

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000387065	SCV000340885	pathogenic	not provided	2016-04-27	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761295	SCV000891269	pathogenic	Exudative vitreoretinopathy 4	2018-10-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000387065	SCV001225523	pathogenic	not provided	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys913Leufs*73) in the LRP5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LRP5 are known to be pathogenic (PMID: 11719191, 16252235, 25711638). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal dominant osteoporosis with familial exudative vitreoretinopathy and autosomal recessive osteoporosis pseudoglioma (PMID: 16252235, 25711638). ClinVar contains an entry for this variant (Variation ID: 287187). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003612	SCV002802851	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	2024-06-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000387065	SCV003930239	pathogenic	not provided	2023-05-27	criteria provided, single submitter	clinical testing	Has been reported with a second pathogenic variant in a patient with pseudoglioma; however phase of the two variants was not determined in this study (Ai et al., 2005); Has also been reported as a single heterozygous variant in a patient with recurrent fractures, and in a second patient with a diagnosis of FEVR (Bardai et al., 2017; Salvo et al., 2015); Published functional studies suggest a damaging effect with this variant resulting in a protein with lower activity compared to wild-type protein (Korvala et al., 2012); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28378289, 16252235, 22487062, 25711638, 35328049, 35753512)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786658	SCV005400464	pathogenic	Osteoporosis with pseudoglioma	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with exudative vitreoretinopathy 4 (FEVR; MIM#601813) and osteoporosis-pseudoglioma syndrome (OPPG; MIM#259770); and autosomal dominant osteopetrosis (MIM#607634), respectively (PMID: 31827910, 23744590). (I) 0108 - This gene is associated with both recessive and dominant disease. Exudative vitreoretinopathy 4 (MIM#601813) can be both autosomal dominant or recessive and is considered to be part of the spectrum of autosomal recessive osteoporosis-pseudoglioma syndrome (MIM#259770). There is currently no clear genotype-phenotype correlation distinguishing these two conditions. Instead, the functional severity of the variant determines the phenotypic consequences (PMID: 31827910). Missense variants clustered within the first b-propeller extracellular domain are associated with autosomal dominant osteopetrosis (MIM#607634; PMID: 23744590). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported for gain of function variants (PMID 23744590) and FEVR (PMID: 25323851). Patients may appear asymptomatic for osteoporosis (PMID: 15824851). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for the condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with FEVR, OPPG, and osteoporosis in the literature (PMIDs: 16252235, 25711638, 35328049, 15824851). (SP) 1206 - This variant has been shown to be paternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign