ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1019_1020delinsTG (p.Cys340Leu) (rs879254758)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237320 SCV000295142 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 RCV000237320 SCV000503280 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing Index case (homozygote) = 1 , family members = 5 with co-segregation (2 homozygotes in the family)
Invitae RCV001203165 SCV001374316 pathogenic Familial hypercholesterolemia 2019-07-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with leucine at codon 340 of the LDLR protein (p.Cys340Leu). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 23535506) and has been observed in an unrelated individual affected with this condition (PMID: 20809525). ClinVar contains an entry for this variant (Variation ID: 251599). 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). For these reasons, this variant has been classified as Pathogenic.

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