ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.647G>A (p.Cys216Tyr) (rs879254611)

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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 RCV000237153 SCV000294845 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 RCV000237153 SCV000503195 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family member = 6 / Software predictions: Damaging
Fundacion Hipercolesterolemia Familiar RCV000237153 SCV000607479 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000791421 SCV000752406 likely pathogenic Familial hypercholesterolemia 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 216 of the LDLR protein (p.Cys216Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypercholesterolemia (PMID: 14974088). ClinVar contains an entry for this variant (Variation ID: 251346). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Cys216 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 18096825, 15241806), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences RCV000237153 SCV001467723 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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