rs773658037
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000527.5(LDLR):c.1247G>A(p.Arg416Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R416W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1247G>A | p.Arg416Gln | missense_variant | 9/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1247G>A | p.Arg416Gln | missense_variant | 9/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251176Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135864
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461620Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727126
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74288
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:7
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Sep 04, 2024 | 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). - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jan 21, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 14, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | 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. - |
Familial hypercholesterolemia Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Nov 03, 2020 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 08, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | 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; Invitae). This variant is also known as p.R395Q. ClinVar contains an entry for this variant (Variation ID: 251752). 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%. 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. - |
Homozygous familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 06, 2019 | 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2022 | 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) - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at