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

gnomAD frequency: 0.00003  dbSNP: rs773658037

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237115	SCV000295324	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000437123	SCV000520999	likely pathogenic	not provided	2022-09-29	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; Also known as p.(R395Q); This variant is associated with the following publications: (PMID: 15241806, 31589614, 30586733, 22390909, 32719484, 32041611, 33303402, 11810272, 9452095, 22294733, 10090484, 33740630, 20506408, 29353225, 31345425, 31491741, 32660911)
Fundacion Hipercolesterolemia Familiar	RCV000237115	SCV000607580	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001182458	SCV001347902	likely pathogenic	Familial hypercholesterolemia	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 416 of the LDLR protein. This variant is also known as p.Arg395Gln in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 1 of the LDLR protein (a.a. 397-438), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 9452095, 11810272, 15241806, 20506408, 22294733, 29353225, 31345425, 31491741, 32660911, 36446894; Color internal data). This variant has been identified in 5/282548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg416Trp, is considered to be disease-causing (ClinVar variation ID: 183110), indicating that arginine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001182458	SCV001380378	pathogenic	Familial hypercholesterolemia	2025-01-14	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 416 of the LDLR protein (p.Arg416Gln). This variant is present in population databases (rs773658037, gnomAD 0.005%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452095, 10090484, 11810272, 15241806, 20506408, 22294733, 22390909, 29353225, 31345425, 31491741, 32660911; internal data). 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 p.R395Q. ClinVar contains an entry for this variant (Variation ID: 251752). 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.Arg416 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 11196104, 11668640, 21376320, 23375686, 25921077). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000237115	SCV001422632	likely pathogenic	Hypercholesterolemia, familial, 1	2024-09-04	criteria provided, single submitter	curation	The p.Arg416Gln (sometimes called p.Arg395Gln) variant in LDLR has been reported in >10 individuals with familial hypercholesterolemia (PMID: 20506408, 22294733, 9452095, 15241806, 11810272), and has been identified in 0.001% (1/91082) of South Asian 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 or pathogenic in ClinVar by multiple submitters (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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PP3_moderate, PM2_supporting (Richards 2015).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000237115	SCV001432622	pathogenic	Hypercholesterolemia, familial, 1	2019-01-21	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000237115	SCV002022674	likely pathogenic	Hypercholesterolemia, familial, 1	2022-02-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000237115	SCV004820285	likely pathogenic	Hypercholesterolemia, familial, 1	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 416 of the LDLR protein. This variant is also known as p.Arg395Gln in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 1 of the LDLR protein (a.a. 397-438), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 9452095, 11810272, 15241806, 20506408, 22294733, 29353225, 31345425, 31491741, 32660911, 36446894, 38003014; Color internal data). This variant has been identified in 5/282548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg416Trp, is considered to be disease-causing (ClinVar variation ID: 183110), indicating that arginine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017554	SCV004847999	likely pathogenic	Homozygous familial hypercholesterolemia	2019-08-06	criteria provided, single submitter	clinical testing	The p.Arg416Gln variant in LDLR has been reported in 1 individual with early onset myocardial infarction and at least 4 individuals with familial hypercholesterolemia (FH), including 1 individual with FH who also carried a nonsense variant in LDLR (Thiart 1998, Fouchier 2001, Mozas 2004, Junyent 2008, Huijgen 2012, Hollants 2012, Pek 2017). Additionally, in a study of 80 Dutch individuals who were either carriers of this variant or non-carrier first degree relatives, LDL-C levels were found to be significantly higher in carriers as compared to non-carriers (4.2 mmol/l in carriers vs. 3.0 mmol/l in non-carrier first degree relatives, p<0.001); however, the absolute number of carriers vs. noncarriers was not provided (Huijgen 2010). This variant has also been reported in ClinVar (Variation ID: 251752) and has been identified in 0.005% (1/19940) of East Asian chromosomes and 0.002% (3/128928) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Finally, a different variant involving this codon (p.Arg416Trp) meets criteria to be classified as pathogenic for FH, suggesting that changes to this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2, PM5, PS4_Moderate.
Ambry Genetics	RCV004020962	SCV004897965	likely pathogenic	Cardiovascular phenotype	2024-06-03	criteria provided, single submitter	clinical testing	The p.R416Q variant (also known as c.1247G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1247. The arginine at codon 416 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Thiart R et al. Hum Mutat, 1998;Suppl 1:S232-3; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Mozas P et al. Hum Mutat, 2004 Aug;24:187; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116; external communication; Ambry internal data). 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001182458	SCV005045745	likely pathogenic	Familial hypercholesterolemia	2020-11-03	criteria provided, single submitter	clinical testing	The c.1247G>A (p.Arg416Gln) variant in the LDLR gene, that encodes for low density lipoprotein receptor, has been identified in several unrelated individuals (>10) with Familial Hypercholesterolemia (PMID:11810272, 22294733, 9452095, 15241806, 29353225, 31345425, 31491741, 32660911, 30293936, 20506408, 10090484). This variant has also been reported in compound heterozygous with another loss of function variant (p.Gln154*) in two individuals with FH (PMID: 27784735, 18096825). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.786). This variant is found to be rare (5/282548; 0.0000177) in the general population database, gnomAD and interpreted as likely pathogenic/ pathogenic by several submitters in the ClinVar database (ClinVar ID: 251752). Therefore, the c.1247G>A (p.Arg416Gln) variant in LDLR gene is classified as likely pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796128	SCV005418145	likely pathogenic	Hypercholesterolemia, familial, 4; Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PS4_Moderate+PP3+PM2+PM5
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000437123	SCV005625809	likely pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	The LDLR c.1247G>A (p.Arg416Gln) variant has been reported in the published literature in (PMID: 10090484 (1999), 15241806 (2004), 29353225 (2018), 31345425 (2019), 31491741 (2019), 33740630 (2021)). The frequency of this variant in the general population, 0.000023 (3/128928 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237115	SCV000606373	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research