rs121908042
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.326G>A(p.Cys109Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,052 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. C109R) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.326G>A | p.Cys109Tyr | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.326G>A | p.Cys109Tyr | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250250Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135616
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461052Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726850
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 01, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jul 22, 2008 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 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 C88Y; This variant is associated with the following publications: (PMID: 25487149, 17094996, 20145306, 19837725, 21310417, 24075752, 17539906, 22883975, 23054246, 11313767, 9544745, 9409298, 33740630, 33418990, 34037665, 32041611, 12459547, 2988123, 24956927) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 07, 2023 | The frequency of this variant in the general population, 0.000004 (1/250250 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 9544745 (1998), 11313767 (2001), 16465405 (2006), 21310417 (2011), 22883975 (2012), 23054246 (2012), 33418990 (2021)), including one compound heterozygous individual (PMID: 22883975 (2012)). It was also reported in individuals with autosomal dominant hypercholesterolemia (PMID: 20145306 (2010), 33740630 (2021)), and coronary artery disease (PMID: 27050191 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 24, 2024 | The c.326G>A (p.C109Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 326, causing the cysteine (C) at amino acid position 109 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250250) total alleles studied. The highest observed frequency was 0.001% (1/112912) of European (non-Finnish) alleles. This alteration, which is also known at p.C88Y, has been reported in individuals with FH (Sun, 1998; Heath, 2001; Sozen, 2004; Taylor, 2007; Chmara, 2010; Hooper, 2012; Norsworthy, 2014; Do, 2015; Dron, 2020; Meshkov, 2021; Sturm, 2021; Leren, 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 3 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 likely pathogenic. - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 109 of the LDLR protein (p.Cys109Tyr). This variant is present in population databases (rs121908042, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9544745, 11313767, 20145306, 21310417, 22883975, 24956927). This variant is also known as Cys88Tyr. ClinVar contains an entry for this variant (Variation ID: 226319). 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 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). This variant disrupts the p.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, 12009418), which suggests that this may be a clinically significant amino acid residue. 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