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

dbSNP: rs879254667

Total submissions: 19

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001190236	SCV001393260	pathogenic	Familial hypercholesterolemia	2024-11-19	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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as Q233P and FH Reggio Emilia-2. ClinVar contains an entry for this variant (Variation ID: 251437). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. 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	RCV000237699	SCV002017110	pathogenic	Hypercholesterolemia, familial, 1	2022-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392740	SCV002673773	pathogenic	Cardiovascular phenotype	2024-06-27	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 of this variant have 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 structural stability (Rudenko G et al. Science, 2002 Dec;298:2353-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000237699	SCV004812194	pathogenic	Hypercholesterolemia, familial, 1	2024-04-03	criteria provided, single submitter	clinical testing	We observed a heterozygous NM_000527:c.761A>C (p.Gln254Pro) genetic variant in the LDLR gene on WES data in a 56-y.o. female proband diagnosed with hypercholesterolemia and Brugada-like pattern on ECG. The c.761A>C (p.Gln254Pro) genetic variant in the LDLR gene is not observed at significant frequency in large population cohorts (gnomAD v4.0.0). ClinVar contains an entry for this variant (Variation ID: 251437) observed in patients with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 22698793, 23375686, 30415195). 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). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237699	SCV005368267	pathogenic	Hypercholesterolemia, familial, 1	2022-07-26	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM1,PM5,PM2_SUP,PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001190236	SCV005395832	pathogenic	Familial hypercholesterolemia	2024-09-17	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.761A>C (p.Gln254Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes (gnomAD). c.761A>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Mollaki_2014, DErasmo_2024). 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. The following publications have been ascertained in the context of this evaluation (PMID: 38374534, 25463123). ClinVar contains an entry for this variant (Variation ID: 251437). Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000237699	SCV005426470	pathogenic	Hypercholesterolemia, familial, 1	2024-03-08	criteria provided, single submitter	clinical testing	The c.761A>C (p.Gln254Pro) variant, also known as p.Gln233Pro and FH Reggio Emilia-2, in the LDLR gene that encodes for low density lipoprotein receptor, has been identified in multiple unrelated individuals (>15) affected with Familial Hypercholesterolemia (FH) (PMID: 10978268, 11524740, 14974088,15200491, 16542394, 19446849, 19319977, 21310417, 21925044, 23375686), including one homozygote (PMID: 23375686). This variant has also been observed in compound heterozygous status (with an established pathogenic variant, p.Cys681* [ClinVar ID: 3699]) in an individual with severe FH (PMID: 31578082). Functional studies using lymphocytes derived from the patient harboring these compound heterozygous variants revealed reduced overall LDLR expression (<60%), reduced LDL binding and intake (<40%) (PMID: 31578082). In-silico computational prediction tools suggest that the p.Gln254Pro variant may have deleterious effect on the protein function (REVEL score: 0.953). This variant is found to be absent in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 251437). Therefore, the c.761A>C (p.Gln254Pro) variant in LDLR gene is classified as pathogenic.
GeneDx	RCV005001026	SCV005626463	pathogenic	not provided	2024-07-11	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia in published literature, also reported as FH Reggio Emilia-2 and Q233P due to alternative nomenclature (PMID: 19319977, 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 22698793, 23375686, 23510778, 25463123, 30415195, 31578082); Observed in homozygous state and compound heterozygous state with a pathogenic variant on the opposite allele (in trans) in individuals with a clinical diagnosis of HoFH in published literature (PMID: 31578082, 23375686); Published functional studies demonstrate a damaging effect due to abolished LDL binding and uptake (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15200491, 16542394, 10978268, 11754108, 14974088, 19446849, 21310417, 21925044, 22698793, 23375686, 23510778, 25463123, 30415195, 31447099, 34426522, 32977124, 32770674, 33740630, 34037665, 37589137, 34297352, 37409534, 34363016, 35379577, 33955087, 38939573, 35222550, 37523181, 19319977, 31578082)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237699	SCV000606217	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research