rs80358320
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_002335.4(LRP5):āc.4081T>Gā(p.Cys1361Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,702 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 Likely pathogenic (ā ). 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. C1361W) has been classified as Likely 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.4081T>G | p.Cys1361Gly | missense_variant | 19/23 | ENST00000294304.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.4081T>G | p.Cys1361Gly | missense_variant | 19/23 | 1 | NM_002335.4 | P1 | |
LRP5 | ENST00000529993.5 | c.*2687T>G | 3_prime_UTR_variant, NMD_transcript_variant | 19/23 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251262Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135840
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1461460Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727042
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74378
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 30, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1361 of the LRP5 protein (p.Cys1361Gly). This variant is present in population databases (rs80358320, gnomAD 0.008%). This missense change has been observed in individuals with autosomal dominant familial exudative vitreoretinopathy (PMID: 15024691; Invitae). ClinVar contains an entry for this variant (Variation ID: 963333). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LRP5 function (PMID: 16252235). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at