ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.691T>G (p.Cys231Gly)

dbSNP: rs746091400
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237108 SCV000294911 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237108 SCV000322912 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000237108 SCV000540755 likely pathogenic Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys216 and Cys231.
Invitae RCV001857824 SCV002149411 pathogenic Familial hypercholesterolemia 2021-09-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys231 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10422804, 10782930, 19073363), 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: 251397). This variant is also known as C210G. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10422804, 11313767, 22698793). This variant is present in population databases (rs746091400, ExAC 0.01%). This sequence change replaces cysteine with glycine at codon 231 of the LDLR protein (p.Cys231Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine.
Arcensus RCV000237108 SCV002564613 likely pathogenic Hypercholesterolemia, familial, 1 2013-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002374396 SCV002668203 pathogenic Cardiovascular phenotype 2017-10-23 criteria provided, single submitter clinical testing The p.C231G pathogenic mutation (also known as c.691T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 691. The cysteine at codon 231 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration is located in the ligand binding domain, and is expected to disrupt a disulfide bond. This alteration, also referred to as C210G, has been reported in multiple individuals with familial hypercholesterolemia (FH), and has been reported as commonly occurring in Norwegian FH cohorts (Sundvold H et al. Hum Mutat. 1996;7:70-1; Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Dušková L et al. Atherosclerosis. 2011;216:139-45; Tichý L et al. Atherosclerosis. 2012;223(2):401-8). In addition, other alterations affecting this amino acid (C231Y, C231R, and C231W) have also been reported in association with FH (Shin JA et al. Clin Genet. 2000;57(3):225-9; Wang L et al. Nutr Metab Cardiovasc Dis. 2009;19(6):391-400; Marduel M et al. Hum Mutat. 2010;31(11):E1811-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001857824 SCV003922713 pathogenic Familial hypercholesterolemia 2023-03-27 criteria provided, single submitter clinical testing Variant summary: LDLR c.691T>G (p.Cys231Gly) results in a non-conservative amino acid change located in the fifth class A repeat (IPR002172) of the encoded protein sequence. The class A repeats form the binding sites for LDL and contain six cysteine residues involved in disulfide bond formation that are required for structural integrity (InterPro). Numerous missense changes affecting cysteine residues within LDLR class A repeats are found among patients with hypercholesterolemia (HGMD), in addition, other variants affecting the same residue (Cys231), have been reported in affected individuals (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246490 control chromosomes (gnomAD). The variant, c.691T>G (aka. C210G), has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Heath_2001, Tichy_2012, Leren_2021), and was described as a frequent founder variant in Norwegian FH patients (Leren_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=2) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237108 SCV000606205 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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