chr19-11113612-T-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.1436T>C(p.Leu479Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,768 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L479Q) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1436T>C | p.Leu479Pro | missense_variant | 10/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1436T>C | p.Leu479Pro | missense_variant | 10/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461768Hom.: 0 Cov.: 35 AF XY: 0.00000963 AC XY: 7AN XY: 727192
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 479 of the LDLR protein (p.Leu479Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 11668627, 16389549, 20736250; Invitae). This variant is also known as L458P. ClinVar contains an entry for this variant (Variation ID: 251840). 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. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at