Submissions for variant NM_002335.4(LRP5):c.724G>A (p.Ala242Thr)

dbSNP: rs121908670

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000383760	SCV000329406	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing	The A242T variant in the LRP5 gene has been report previous in numerous patients diagnosed with high bone mass, osteopetrosis, osteosclerosis, endosteal hyperostosis, and Van Buchem disease (Wang et al., 2013; Gregson et al., 2016; Van et al., 2003). In virtro functional studies demonstrated that protein harboring the A242T variant undergoes post-translational modification at a significantly lower level than wild-type and has significantly reduced interactions DKK1 protein in comparison to wild-type (Ai et al., 2005). The A242T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A242T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000006660	SCV001934303	likely pathogenic	Worth disease	2020-11-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000383760	SCV003440555	likely pathogenic	not provided	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 242 of the LRP5 protein (p.Ala242Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant high bone mass syndromes (PMID: 12579474, 23318847, 26348019, 37334733). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6282). 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%. Experimental studies have shown that this missense change affects LRP5 function (PMID: 18521528). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM	RCV000006660	SCV000026843	pathogenic	Worth disease	2003-03-01	no assertion criteria provided	literature only
OMIM	RCV000006661	SCV000026844	pathogenic	Autosomal dominant osteopetrosis 1	2003-03-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000383760	SCV001977780	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000383760	SCV001978686	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742220	SCV005367153	pathogenic	LRP5-related disorder	2024-08-02	no assertion criteria provided	clinical testing	The LRP5 c.724G>A variant is predicted to result in the amino acid substitution p.Ala242Thr. This variant has been reported to be causative for endosteal hyperostosis, osteopetrosis, and osteosclerosis phenotypes in an autosomal dominant manner in multiple families (van Wesenbeeck et al. 2003. PubMed ID: 12579474; Wang et al. 2013. PubMed ID: 23318847; Gregson et al. 2015. PubMed ID: 26348019). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.