chr19-11105590-G-C
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.684G>C(p.Glu228Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E228K) has been classified as Pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.684G>C | p.Glu228Asp | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.684G>C | p.Glu228Asp | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Jul 18, 2018 | The mutation at the protein level at position 228 leads to the amino acid substitution glutamic acid against aspartic acid (p.Glu228Asp, E228D). This change has not been described in the literature so far. However, prediction programs classify this mutation as pathogenic (Mutationtaster, SpliceSiteFinder). In addition, the mutation is located in a conserved region (Ser-Asp-Glu), which is essential for receptor function and in which many other pathogenic mutations have already been described. PMID: 20354512, 2988123, 28502510 - |
Likely pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu228 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2318961, 21475731, 21722902, 22390909, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects LDLR function (PMID: 31106925). 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 LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 523724). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 28502510, 28964736, 31106925; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 228 of the LDLR protein (p.Glu228Asp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at