ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.761A>C (p.Gln254Pro) (rs879254667)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237699 SCV000294955 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 RCV000237699 SCV000503231 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237699 SCV000540757 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237699 SCV000583736 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844739 SCV000712914 likely pathogenic Homozygous familial hypercholesterolemia 2017-03-13 criteria provided, single submitter clinical testing The p.Gln254Pro variant in LDLR has been reported in the heterozygous state in 9 individuals with familial hypercholesterolemia, as well as one homozygote (Bert olini 2000, Dedoussis 2004, Brusgaard 2006, Diakou 2011, Tichy 2012, Bertolini 2 013. In addition, this variant has been reported in a consanguineous family alon g with a second hypercholesterolemia variant (LDLRAP1 p.Gly136X). In this family , disease severity correlated with the various combinations of heterozygosity or homozygosity for the two variants (Soufi 2013). The p.Gln254Pro variant has als o been reported in ClinVar (Variation ID 251437) and was absent from large popul ation studies. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Gln254Pro variant is likely pathogenic.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000237699 SCV000987041 pathogenic Familial hypercholesterolemia 1 2018-12-19 criteria provided, single submitter clinical testing The mutation at protein level leads to an amino acid exchange of glutamine to proline at position 254 (233rd amino acid of the mature protein) in the LDL receptor. This change has already been described in the literature as FH Reggio Emilia-2, as well as in patients with familial hypercholesterolaemia. We observed this variant in a patient with TC up to 360 mg/dl and LDL-C approx 300 mg/dl at the age of 55. PMID: 14974088, 11754108, 23375686
Color Health, Inc RCV001190236 SCV001357683 pathogenic Familial hypercholesterolemia 2019-10-10 criteria provided, single submitter clinical testing
Invitae RCV001190236 SCV001393260 pathogenic Familial hypercholesterolemia 2019-04-09 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 254 of the LDLR protein (p.Gln254Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with familial hypercholesterolemia (PMID: 10978268, 10978268, 25463123, 11754108, 21925044, 19319977, 19446849, 14974088). This variant is also known as Q233P and FH Reggio Emilia-2 in the literature. ClinVar contains an entry for this variant (Variation ID: 251437). 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.Gln233 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000237699 SCV001653608 likely pathogenic Familial hypercholesterolemia 1 2021-05-24 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000237699 SCV001754783 likely pathogenic Familial hypercholesterolemia 1 2019-09-26 criteria provided, single submitter clinical testing The c.761A>C (p.Gln254Pro) variant in the LDLR gene has been described as FH Reggio Emilia-2 in the literature (PMID: 10978268) and reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 23375686, 23510778). This variant is absent from general population databases. Multiple lines of in silico algorithms have predicted this p.Gln254Pro change to be deleterious. Therefore, this c.761A>C (p.Gln254Pro) variant is classified as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237699 SCV000606217 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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