rs759025536
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_004525.3(LRP2):c.9733G>T(p.Asp3245Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,016 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3245N) has been classified as Uncertain significance.
Frequency
Consequence
NM_004525.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.9733G>T | p.Asp3245Tyr | missense_variant | 50/79 | ENST00000649046.1 | |
LRP2 | XM_011511183.4 | c.9733G>T | p.Asp3245Tyr | missense_variant | 50/78 | ||
LRP2 | XM_047444340.1 | c.8809G>T | p.Asp2937Tyr | missense_variant | 50/79 | ||
LRP2 | XM_011511184.3 | c.7444G>T | p.Asp2482Tyr | missense_variant | 35/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.9733G>T | p.Asp3245Tyr | missense_variant | 50/79 | NM_004525.3 | P1 | ||
LRP2 | ENST00000649153.1 | c.634G>T | p.Asp212Tyr | missense_variant, NMD_transcript_variant | 2/30 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727228
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 19, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 LRP2 protein function. ClinVar contains an entry for this variant (Variation ID: 437989). This missense change has been observed in individual(s) with retinal dystrophy (PMID: 28041643). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 3245 of the LRP2 protein (p.Asp3245Tyr). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with another missense variant in LRP2 in a patient with retinal dystrophy in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Carss et al., 2017); This variant is associated with the following publications: (PMID: 32581362, 28041643) - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at