rs753248521
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP3_StrongPP5_Strong
The NM_000527.5(LDLR):c.1070A>G(p.Glu357Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E357K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1070A>G | p.Glu357Gly | missense_variant | 8/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1070A>G | p.Glu357Gly | missense_variant | 8/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251270Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | The NM_000527.5(LDLR):c.1070A>G (p.Glu357Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4-supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000008800 (0.00088%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.984. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. PS4_supporting - Variant meets PM2 and is identified in 4 index cases (3 cases with Simon-Broome criteria of possible FH in PMID: 34456049 (Marco-Benedí et al., 2022), Spain; 1 case with internationally accepted criteria (Defesche et al, 2000) in PMID: 16250003 (Fouchier et al, 2005), The Netherlands. - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at