ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) (rs552422789)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000223047 SCV000271917 uncertain significance not specified 2019-04-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg406Gln variant in LDLR has been reported in 4 individuals with hypercholesterolemia (Thiart 2000, Tosi 2007, Abul Husn 2016, Pek 2017). It has also been identified in 0.006% (1/16224) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 228798). Computational prediction tools and conservation analysis suggest that the p.Arg406Gln variant may impact the protein. In addition, splicing prediction tools predict this variant results in the generation of a novel 3' splice site. However, the results of these computational tools are not predictive enough to determine pathogenicity. An additional variant involving this codon (p.Arg406Trp) has been identified in individuals with hypercholesterolemia and is classified as pathogenic by this laboratory, suggesting variation at this site may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PM2_Supporting, PP3, PS4_Supporting.
LDLR-LOVD, British Heart Foundation RCV000238261 SCV000295307 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 RCV000238261 SCV000503318 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 3 with unclear co-segregation / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238261 SCV000583807 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000238261 SCV000607576 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001381623 SCV001580100 pathogenic Familial hypercholesterolemia 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 406 of the LDLR protein (p.Arg406Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs552422789, ExAC 0.01%). This variant has been observed in several individuals affected with LDLR-related conditions (PMID: 10882754, 17094996, 28008010). ClinVar contains an entry for this variant (Variation ID: 228798). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg406 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8882879, 25461735, 26343872). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238261 SCV000606363 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000238261 SCV001423091 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Arg406Gln variant in LDLR has been reported in at least 9 individuals (including 1 African individual) with Familial Hypercholesterolemia (PMID: 17094996, 10882754, 23680767, 28008010; Variation ID: 228798), and has been identified in 0.001593% (4/251042) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs552422789). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 228798). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional variants with a different amino acid change at the same position, p.Arg406Pro and p.Arg406Trp, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 226352, 226351). cDNA analysis of an individual with a synonymous variant in the same codon suggests that this region may be important for splicing (PMID: 18400033). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PS4_supporting, PP3 (Richards 2015).

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