rs201320326
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PP2PP3_StrongPP5_Moderate
The NM_002335.4(LRP5):c.1199C>A(p.Ala400Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A400V) has been classified as Uncertain significance.
Frequency
Consequence
NM_002335.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP5 | NM_002335.4 | c.1199C>A | p.Ala400Glu | missense_variant | 6/23 | ENST00000294304.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.1199C>A | p.Ala400Glu | missense_variant | 6/23 | 1 | NM_002335.4 | P1 | |
LRP5 | ENST00000529993.5 | c.1199C>A | p.Ala400Glu | missense_variant, NMD_transcript_variant | 6/23 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461746Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727194
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 400 of the LRP5 protein (p.Ala400Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals 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: 967240). 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. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at