ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1247G>A (p.Arg416Gln) (rs773658037)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237115 SCV000295324 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000437123 SCV000520999 pathogenic not provided 2016-12-13 criteria provided, single submitter clinical testing The R416Q variant in the LDLR gene has been reported previously in association with familial hypercholesterolemia (Thiart et al., 1998; Fouchier et al., 2001; Hollants et al., 2012; Huijgen et al., 2012). The R416Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R416Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same codon (R416W, R416P, R416L) have been reported in the Human Gene Mutation Database in association with familial hypercholesterolemia (Stenson et al., 2014), supporting the functional importance of this codon. We interpret R416Q as a pathogenic variant
Fundacion Hipercolesterolemia Familiar RCV000237115 SCV000607580 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV001182458 SCV001347902 likely pathogenic Familial hypercholesterolemia 2020-09-24 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg395Gln in the mature protein) replaces arginine with glutamine at codon 416 in the LDLR type B repeat 1 of the LDL 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in seven individuals affected with familial hypercholesterolemia (PMID: 9452095, 11810272, 15241806, 20506408, 22294733, 29353225, 32660911). This variant has been identified in 5/282548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variant at the same position p.Arg416Trp is a well established Pathogenic variant (Clinvar variation ID 183110). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV001182458 SCV001380378 uncertain significance Familial hypercholesterolemia 2019-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 416 of the LDLR protein (p.Arg416Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs773658037, ExAC 0.01%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 9452095, 22390909, 10090484, 15241806, 20506408, 11810272, 29353225). This variant is also known as R395Q in the literature. ClinVar contains an entry for this variant (Variation ID: 251752). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg416 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20663204, 23375686, 21376320, 9104431, 25378237, 25921077, 11196104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000237115 SCV001432622 pathogenic Familial hypercholesterolemia 1 2019-01-21 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237115 SCV000606373 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000237115 SCV001422632 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Arg416Gln (sometimes called p.Arg395Gln) variant in LDLR has been reported in at least 84 individuals (including 1 German, 1 Spanish, and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 20506408, 22294733, 9452095, 15241806, 11810272), and has been identified in 0.005015% (1/19940) of East Asian chromosomes, 0.003982% (1/25114) of European (Finnish) chromosomes, and 0.002327% (3/128928) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773658037). 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 likely pathogenic and pathogenic in ClinVar (Variation ID: 251752). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4, PP3 (Richards 2015).

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