rs80358313
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1PM1PM2PM5PP2PP3_Strong
The NM_002335.4(LRP5):c.1828G>A(p.Gly610Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G610W) has been classified as Pathogenic.
Frequency
Consequence
NM_002335.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP5 | NM_002335.4 | c.1828G>A | p.Gly610Arg | missense_variant | 9/23 | ENST00000294304.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.1828G>A | p.Gly610Arg | missense_variant | 9/23 | 1 | NM_002335.4 | P1 | |
LRP5 | ENST00000529993.5 | c.*434G>A | 3_prime_UTR_variant, NMD_transcript_variant | 9/23 | 1 | ||||
LRP5 | ENST00000528890.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251164Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461810Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727218
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74324
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 610 of the LRP5 protein (p.Gly610Arg). This variant is present in population databases (rs80358313, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant osteoporosis with retinopathy and autosomal recessive osteoporosis-pseudoglioma syndrome (PMID: 15981244, 16252235, 20340138). 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: 6294). 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. Experimental studies have shown that this missense change affects LRP5 function (PMID: 16252235). For these reasons, this variant has been classified as Pathogenic. - |
Exudative vitreoretinopathy 4, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2005 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at