ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.324_325delinsTC (p.Cys109Arg) (rs879254476)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237956 SCV000294628 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237956 SCV000503139 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 6 , family members = 6 with co-segregation
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000237956 SCV000987024 pathogenic Familial hypercholesterolemia 1 2018-05-11 criteria provided, single submitter clinical testing The deletion of the two nucleotides GT and the insertion of the two nucleotides TC at position 324 leads to the amino acid exchange cysteine to arginine (p.Cys109Arg). This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. We diagnosed this variant in a patient with FH at the age of 17. PMID: 11313767, 14974088, 16314194
Invitae RCV001207725 SCV001379090 pathogenic Familial hypercholesterolemia 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 109 of the LDLR protein (p.Cys109Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 14974088, 19843101, 11313767, 22698793, 20145306). ClinVar contains an entry for this variant (Variation ID: 251154). 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: 12009418, 9544745, 1131376), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000237956 SCV001440381 likely pathogenic Familial hypercholesterolemia 1 2019-01-01 criteria provided, single submitter clinical testing

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