19-11107400-T-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000527.5(LDLR):c.826T>C(p.Cys276Arg) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C276S) has been classified as Uncertain significance.
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.826T>C | p.Cys276Arg | missense_variant | 6/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.826T>C | p.Cys276Arg | missense_variant | 6/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
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 | subjects mutated among 2600 FH index cases screened = 2 / FH-Ceva / Software predictions: Damaging - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 13, 2024 | Criteria applied: PM5_STR,PS4_MOD,PM1,PM3,PM2_SUP,PP3 - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.C255R; This variant is associated with the following publications: (PMID: 30710474, 23375686, 10978268) - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys276 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10634824, 26361156), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251479). This variant is also known as C255R. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10978268). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 276 of the LDLR protein (p.Cys276Arg). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2017 | Variant summary: The LDLR c.826T>C (p.Cys276Arg) variant involves the alteration of a conserved nucleotide that results in the alteration of a cysteine residue at the protein level that is highly conserved across species (Bertolini 2013). The variant is located in the ligand-binding domain of the LDL receptor (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these predictions have not been evaluated for functional impact by in vivo/vitro studies. This variant is absent in 246246 control chromosomes (gnomAD). The variant has been reported in individuals presented with hypercholesterolemia in heterozygous form (Bertolini 2003), however without providing clear evidence for causality. One clinical diagnostic laboratoy and a databases classified this variant as likely pathogenic, without evidence for independent evaluation. Variants involving the same codon such as C276G, C276F, C276W, and C276Y have been reported in affected individuals suggesting the functional importance of this codon. Taken together, this variant is classified as VUS-possibly pathogenic, until additional evidence becomes available. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at