rs879255025
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000527.5(LDLR):c.1796T>C(p.Leu599Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,882 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L599W) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1796T>C | p.Leu599Ser | missense_variant | 12/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1796T>C | p.Leu599Ser | missense_variant | 12/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461882Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jan 22, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
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 | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2022 | The p.L599S variant (also known as c.1796T>C), located in coding exon 12 of the LDLR gene, results from a T to C substitution at nucleotide position 1796. The leucine at codon 599 is replaced by serine, an amino acid with dissimilar properties. This variant (also referred to as L578S and FH London-5) co-occurred with an LDLR gross deletion in an individual with total cholesterol of 27mmol/L and reported LDL-R activity 5-15% of normal (Hobbs HH et al. Hum Mutat, 1992;1:445-66, Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). This variant has also been detected in additional individuals from familial hypercholesterolemia (FH) cohorts with suspected heterozygous FH (Webb JC et al. J Lipid Res, 1996 Feb;37:368-81; Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Laurie AD et al. Clin Biochem, 2009 Apr;42:528-35; Trinder M et al. J Am Coll Cardiol. 2019 Jul;74(4):512-522). Based on internal structural analysis, this variant is predicted to be destabilizing (Jeon H et al. Nat Struct Biol. 2001 Jun;8(6):499-504; Rudenko G et al. Science. 2002 Dec;298(5602):2353-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2023 | 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. This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 599 of the LDLR protein (p.Leu599Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 12436241, 19318025, 27680772, 31345425). This variant is also known as L578S. ClinVar contains an entry for this variant (Variation ID: 252035). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at