rs200475391
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_004525.3(LRP2):c.11288A>T(p.Glu3763Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,613,246 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 (★★).
Frequency
Consequence
NM_004525.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRP2 | NM_004525.3 | c.11288A>T | p.Glu3763Val | missense_variant | Exon 59 of 79 | ENST00000649046.1 | NP_004516.2 | |
LRP2 | XM_011511183.4 | c.11159A>T | p.Glu3720Val | missense_variant | Exon 58 of 78 | XP_011509485.1 | ||
LRP2 | XM_047444340.1 | c.10364A>T | p.Glu3455Val | missense_variant | Exon 59 of 79 | XP_047300296.1 | ||
LRP2 | XM_011511184.3 | c.8999A>T | p.Glu3000Val | missense_variant | Exon 44 of 64 | XP_011509486.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRP2 | ENST00000649046.1 | c.11288A>T | p.Glu3763Val | missense_variant | Exon 59 of 79 | NM_004525.3 | ENSP00000496870.1 | |||
LRP2 | ENST00000649153.1 | n.2186A>T | non_coding_transcript_exon_variant | Exon 11 of 30 | ENSP00000497617.1 | |||||
LRP2 | ENST00000650252.1 | n.320A>T | non_coding_transcript_exon_variant | Exon 4 of 24 | ENSP00000496887.1 |
Frequencies
GnomAD3 genomes AF: 0.000356 AC: 54AN: 151858Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251422Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135880
GnomAD4 exome AF: 0.000424 AC: 620AN: 1461388Hom.: 0 Cov.: 31 AF XY: 0.000436 AC XY: 317AN XY: 727036
GnomAD4 genome AF: 0.000356 AC: 54AN: 151858Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 24AN XY: 74152
ClinVar
Submissions by phenotype
not provided Uncertain:3
- -
- -
This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 3763 of the LRP2 protein (p.Glu3763Val). This variant is present in population databases (rs200475391, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with LRP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 520735). 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. 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. -
Donnai-Barrow syndrome Uncertain:2
- -
- -
DSD incomplete virilization Pathogenic:1
- -
LRP2-related disorder Uncertain:1
The LRP2 c.11288A>T variant is predicted to result in the amino acid substitution p.Glu3763Val. This variant was reported in one individual with hypoplastic left heart syndrome, but was also observed in two controls (Supp. Table 7 in Theis et al 2020. PubMed ID: 33006316). This variant was also reported in an individual with 46,XY differences of sex development (Marko HL et al 2022. PubMed ID: 34979047). This variant is reported in 0.044% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Inborn genetic diseases Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at