ClinVar Miner

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

dbSNP: rs879254667
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Total submissions: 14
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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 Hypercholesterolemia, familial, 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 Hypercholesterolemia, familial, 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 Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237699 SCV000583736 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Hypercholesterolemia, familial, 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 Diagnostics, LLC DBA Color Health RCV001190236 SCV001357683 pathogenic Familial hypercholesterolemia 2019-10-10 criteria provided, single submitter clinical testing This missense variant (also known as p.Gln233Pro in the mature protein and as FH-Reggio Emilia-2) replaces glutamine with proline at codon 254 in the LDLR type A repeat 6 of ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant does not affect protein expression at the cellular surface but reduces LDL binding and internalization activity by 80% compared to wild type protein (PMID: 31578082). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 22698793, 23375686, 30415195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV001190236 SCV001393260 pathogenic Familial hypercholesterolemia 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 254 of the LDLR protein (p.Gln254Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 19319977, 19446849, 21925044, 25463123). This variant is also known as Q233P and FH Reggio Emilia-2. ClinVar contains an entry for this variant (Variation ID: 251437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. 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 Hypercholesterolemia, familial, 1 2021-05-24 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000237699 SCV001754783 likely pathogenic Hypercholesterolemia, familial, 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.
Revvity Omics, Revvity Omics RCV000237699 SCV002017110 pathogenic Hypercholesterolemia, familial, 1 2022-04-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV002392740 SCV002673773 pathogenic Cardiovascular phenotype 2020-10-06 criteria provided, single submitter clinical testing The p.Q254P pathogenic mutation (also known as c.761A>C), located in coding exon 5 of the LDLR gene, results from an A to C substitution at nucleotide position 761. The glutamine at codon 254 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple individuals of various ethnic backgrounds with familial hypercholesterolemia (Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Abifadel M et al. Hum. Mutat., 2009 Jul;30:E682-91; Soufi M et al. Gene, 2013 May;521:200-3; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804). Functional studies demonstrated reduced LDL binding and uptake (Banerjee P et al. Arterioscler. Thromb. Vasc. Biol., 2019 11;39:2248-2260). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in ligand binding and structure stability (Rudenko G et al. Science, 2002 Dec;298:2353-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV000237699 SCV002790803 pathogenic Hypercholesterolemia, familial, 1 2022-03-29 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237699 SCV000606217 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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