rs879254558
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.517T>C(p.Cys173Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,748 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. C173S) 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.517T>C | p.Cys173Arg | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.517T>C | p.Cys173Arg | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461748Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727180
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 173 of the LDLR protein (p.Cys173Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11317361, 33740630). This variant is also known as C152R. ClinVar contains an entry for this variant (Variation ID: 251272). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys173 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452094, 11462246, 11810272, 25962062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2017 | Variant summary: The LDLR c.517T>C (p.Cys173Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant and LDL receptor activity in fibroblast from compound heterozygote with p.S265R (known DV) was shown to be 5-15% of wt (Hobbs, 1998). Most of the published reports cite the variant as partially defective allele although now functional studies confirming deleterious impact on the protein function solely by the variant of interest have been published at the time of evaluation. The variant is absent from the large control population datasets of ExAC or gnomAD, but has been reported in multiple affected individuals with biochemically and clinically confirmed FH in heterozygous state (Miltiadous, 2001; Mollaki, 2014) and severe FH in compound heterozygosity with a known pathogenic alleles (Hobbs, 1998; Su, 2009). The c.517T>C is considered to be one of the Greek founder mutations. In addition, a clinical diagnostic laboratory/reputable database classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 27, 2022 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported as a common Greek variant and was identified in multiple individuals affected with familial hypercholesterolemia (PMID: 9544850 (1998), 11317361 (2001), 19837725 (2010), 21925044 (2011), 25463123 (2014), 30108616 (2018)). Functional studies of cultured fibroblasts showed that this variant with a second pathogenic variant retained only 5-15% LDLR activity (PMID: 1301956 (1992)). Based on the available information, this variant is classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2023 | The c.517T>C (p.C173R) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 517, causing the cysteine (C) at amino acid position 173 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, also described as C152R and FH-Greece 1, has been reported in multiple individuals with familial hypercholesterolemia (FH) (Whittall, 2010; Diakou, 2011; Jiang, 2016; Wang, 2016). Another alteration at the same codon, c.519C>G (p.C173W), has been described in multiple individuals with FH (Couture, 1998; Morash, 1998; Sturm, 2021). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 4 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at