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

Genomes: 𝑓 0.000026 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

7
7
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a repeat LDL-receptor class B 1 (size 41) in uniprot entity LDLR_HUMAN there are 61 pathogenic changes around while only 8 benign (88%) in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865
PP5
Variant 19-11113338-G-A is Pathogenic according to our data. Variant chr19-11113338-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113338-G-A is described in Lovd as [Pathogenic]. Variant chr19-11113338-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.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
LDLRENST00000558518.6 linkuse as main transcriptc.1247G>A p.Arg416Gln missense_variant 9/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152062
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251176
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461620
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152062
Hom.:
0
Cov.:
29
AF XY:
0.0000135
AC XY:
1
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Likely pathogenic, criteria provided, single submitterresearchFundacion Hipercolesterolemia FamiliarMar 01, 2016- -
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardSep 04, 2024The 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 submitterresearchBrunham Lab, Centre for Heart and Lung Innovation, University of British ColumbiaJan 21, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 14, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 08, 2024This 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 submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineNov 03, 2020The 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 08, 2023This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024This 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 06, 2019The 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 submitterclinical testingGeneDxSep 29, 2022Not 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 submitterclinical testingAmbry GeneticsJun 03, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.71
D;.;.;.;.;.
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Benign
1.9
L;.;.;.;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.0
D;D;D;D;D;D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0060
D;D;D;D;D;D
Sift4G
Uncertain
0.024
D;D;D;D;D;D
Polyphen
0.95
P;.;.;.;.;.
Vest4
0.56
MVP
1.0
MPC
0.67
ClinPred
0.77
D
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.72
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773658037; hg19: chr19-11224014; COSMIC: COSV52941747; COSMIC: COSV52941747; API