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

gnomAD frequency: 0.00001  dbSNP: rs552422789

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238261	SCV001960924	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-09	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5, PP3, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006164 (0.006%) in African/African American (gnomAD v2.1.1). PM5 - Two other missense variants described in the same codon (accessed 19 August 2020): --- 1 variant classified as Pathogenic by these guidelines. PP3 - REVEL: 0,809. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling Simon-Broome criteria. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (PMID: 10882754 - 1 case with Simon-Broome criteria; PMID: 17094996 - 1 case with Simon-Broome criteria).
Laboratory for Molecular Medicine, Mass General Brigham 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	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	RCV000238261	SCV000503318	uncertain significance	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000238261	SCV000607576	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000238261	SCV001423091	uncertain significance	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	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).
Invitae	RCV001381623	SCV001580100	pathogenic	Familial hypercholesterolemia	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 406 of the LDLR protein (p.Arg406Gln). This variant is present in population databases (rs552422789, gnomAD 0.007%). This missense change has been observed in individuals with LDLR-related conditions (PMID: 10882754, 17094996, 28008010). ClinVar contains an entry for this variant (Variation ID: 228798). 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV002354607	SCV002656838	likely pathogenic	Cardiovascular phenotype	2016-05-05	criteria provided, single submitter	clinical testing	The p.R406Q variant (also known as c.1217G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1217. The arginine at codon 406 is replaced by glutamine, an amino acid with highly similar properties. This variant has been described in unrelated individuals reported to have familial hypercholesterolemia (Thiart R et al. J Med Genet. 2000;37(7):514-9; Durst R et al. Atherosclerosis. 2006;189(2):443-50; Tosi I et al. Atherosclerosis. 2007;194(1):102-11 (reported as p.R385Q in these publications); Pek et al. Atherosclerosis. 2017; [Epub ahead of print]). Other alterations affecting the the same amino acid (p.R406P, c.1217G>C and p.R406W, c.1216C>T) have also been reported in association with hypercholesterolemia (Tosi I et al. Atherosclerosis. 2007;194(1):102-11 (reported as p.R385P); Benito-Vicente A et al. Genet Med. 2015;17(12):980-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000238261	SCV003829642	likely pathogenic	Hypercholesterolemia, familial, 1	2022-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV003325470	SCV004031599	likely pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports that this missense variant has a deleterious effect on splicing; Also known as R385Q; This variant is associated with the following publications: (PMID: 29353225, 34037665, 17094996, 28008010, 16466730, 33418990, 36499307, 10882754)
Color Diagnostics, LLC DBA Color Health	RCV001381623	SCV004358515	likely pathogenic	Familial hypercholesterolemia	2023-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 406 in LDLR type B repeat 1 in EGF precursor homology domain of the LDLR protein. This variant is also known as p.Arg385Gln in the mature protein. Computational prediction suggests that this variant may have a 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 create a new acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 10882754, 17094996, 23680767, 28008010, 29353225, 33418990, 34037665, 36499307, ClinVar SCV000503318.1). Different missense variants affecting the same codon, p.Arg406Trp and p.Arg406Pro, are considered to be disease-causing (ClinVar variation ID: 226351 and 226352), suggesting that arginine at this position is important for LDLR protein function. This variant has been identified in 4/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000238261	SCV004820279	likely pathogenic	Hypercholesterolemia, familial, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 406 in LDLR type B repeat 1 in EGF precursor homology domain of the LDLR protein. This variant is also known as p.Arg385Gln in the mature protein. Computational prediction suggests that this variant may have a 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 create a new acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 10882754, 17094996, 23680767, 28008010, 29353225, 33418990, 34037665, 36499307, ClinVar SCV000503318.1). Different missense variants affecting the same codon, p.Arg406Trp and p.Arg406Pro, are considered to be disease-causing (ClinVar variation ID: 226351 and 226352), suggesting that arginine at this position is important for LDLR protein function. This variant has been identified in 4/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238261	SCV000606363	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research