Submissions for variant NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr)

dbSNP: rs121908042

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211658	SCV000294631	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211658	SCV000484762	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
GeneDx	RCV000521830	SCV000617501	likely pathogenic	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Identified in patients with familial hypercholesterolemia in published literature, although segregation data is largely unavailable (PMID: 9544745, 11313767, 17539906, 17094996, 20145306, 21310417, 23054246, 22883975, 24075752, 24956927, 25487149, 12459547, 2988123); 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.(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, 24956927, 12459547, 2988123)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820331	SCV000961039	pathogenic	Familial hypercholesterolemia	2023-10-28	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002444847	SCV002612497	likely pathogenic	Cardiovascular phenotype	2024-04-24	criteria provided, single submitter	clinical testing	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) (Vill&eacute;ger, 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.
Genetics and Molecular Pathology, SA Pathology	RCV000211658	SCV004175578	pathogenic	Hypercholesterolemia, familial, 1	2021-10-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000521830	SCV004219981	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	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.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000211658	SCV005417140	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PP4+PM1+PP3_Strong
All of Us Research Program, National Institutes of Health	RCV000211658	SCV005426440	pathogenic	Hypercholesterolemia, familial, 1	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys88Tyr in the mature protein) replaces cysteine with tyrosine at codon 109 in the LDLR type A repeat 3 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9026534, 11313767, 17094996, 17539906, 20145306, 22883975, 23833242, 24075752, 33418990, 33740630, 34037665). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia and extensive atherosclerotic cardiovascular disease, a phenotype expected of having two deleterious LDLR variants (PMID: 22883975, 32276786). Additionally, this variant has been reported in an individual affected with coronary artery disease (PMID: 27050191) and in an individual affected with moderately high total cholesterol despite cholesterol-lowering therapy (PMID: 24956927). This variant has been identified in 1/250250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211658	SCV000268557	pathogenic	Hypercholesterolemia, familial, 1	2008-07-22	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211658	SCV000606087	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research