ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1103G>A (p.Cys368Tyr) (rs768430352)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237712 SCV000503297 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 3 , family members = 3 with co-segregation / previously described in association with FH / Software predictions: Damaging
Fundacion Hipercolesterolemia Familiar RCV000237712 SCV000607559 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000237712 SCV000748050 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000781493 SCV000919571 pathogenic Familial hypercholesterolemias 2018-02-28 criteria provided, single submitter clinical testing Variant summary: LDLR c.1103G>A (p.Cys368Tyr) results in a non-conservative amino acid change located in the EGF-like domain, EGF-like calcium-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant of interest was observed in controls with an allele frequency of 4/277340 control chromosomes. This frequency is does exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant. The c.1103G>A variant has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia. 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. Multiple variants at the same codon have been reported as associated with disease (e.g., C368R, C268G, and C368S), as well as nearby codons (e.g., D354G, C364R, and G373D), suggesting a functional importance for this codon and location. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 pathogenic, 2 likely pathogenic, and 2 VUS). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000237712 SCV000824206 pathogenic Familial hypercholesterolemia 2018-06-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 368 of the LDLR protein (p.Cys368Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs768430352, ExAC 0.002%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 1310940, 23064986, 21722902, 25461735, 26081744). This variant is also known as p.Cys347Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 251665). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain 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: 3495735, 4750422). In addition, missense substitutions within the LDLR 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. The p.Cys368 amino acid residue in LDLR has been determined to be clinically significant (PMID: 9452094, 27765764). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000237712 SCV000295220 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237712 SCV000606329 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000237712 SCV000588554 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237712 SCV000583789 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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