rs570942190

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.1246C>T(p.Arg416Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,778 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R416Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 0.809

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]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain 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 chr19-11113338-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 19-11113337-C-T is Pathogenic according to our data. Variant chr19-11113337-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113337-C-T is described in Lovd as [Pathogenic]. Variant chr19-11113337-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-11113337-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1246C>T	p.Arg416Trp	missense_variant	9/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1246C>T	p.Arg416Trp	missense_variant	9/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251158

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461604

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:13

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This missense variant (also known as p.Arg395Trp in the mature protein) replaces arginine with tryptophan at codon 416 in the LDLR type B repeat of the EGF precursor homology domain of the LDLR 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). A functional study has shown that this variant decreases LDLR cell surface expression and LDL uptake, and causes defective LDLR recycling due to protein degradation in lysosomes (PMID 25378237). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515, 27784735, 28104544, 32423031, 33740630, 33955087, 33994402, 34037665, 34407635, 34834584, 36499307). It has been shown that this variant segregates with hypercholesterolemia in multiple Norwegian families (PMID: 9104431). This variant has been identified in 6/251158 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg416Gln, is considered to be disease-causing (ClinVar variation ID: 251752), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	May 22, 2012	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The LDLR c.1246C>T (p.Arg416Trp) variant, also referred to as p.Arg395Trp, has been identified in a heterozygous state in 33 individuals of different ethnicities with either definite or possible familial hypercholesterolemia (FH) (Day et al. 1997; Leren et al. 1997; Wang et al. 2001; Garcia-Garcia et al. 2001; Dedoussis et al. 2004; Tichy et al. 2012; Bertolini et al. 2013). An additional study detected either the p.Arg416Trp variant or one of two other common variants in the LDLR gene in 186 of 1,945 Czech individuals with a probable or definite diagnosis of FH (Goldmann et al. 2010). Leren et al. (1997) also note that the p.Arg416Trp variant segregated with disease in family members of the nine unrelated individuals in their study. The variant was absent from 60 total control individuals and is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies indicated that with the p.Arg416Trp variant, LDLR expression on the cell surface and LDL uptake efficiency were decreased when compared to wildtype, suggesting defective receptor recycling (Etxebarria et al. 2015). Based on the evidence, the p.Arg416Trp variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 13, 2019	- -

not provided

Pathogenic:3Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 21, 2023	The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial or isolated hypercholesterolemia (PMIDs: 36901902 (2023), 34456049 (2022), 35913489 (2022), 35339733 (2022), 33955087 (2021), 34407635 (2021), 33303402 (2021), 33994402 (2021) 33418990 (2021), 34037665 (2021), 33740630 (2021), 32423031 (2020), 31447099 (2019), 30592178 (2019), 31345425 (2019), 29531935 (2018), 28104544 (2017)). Functional studies show the variant impacts LDLR expression and binding (PMIDs: 25378237 (2015)). 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 pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest defective receptor recycling, membrane localization, binding activity, and LDL particle uptake (Etxebarria et al., 2015; Thormaehlen et al., 2015; Galicia-Garcia et al., 2020; Duskova et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R395W; This variant is associated with the following publications: (PMID: 9259195, 17539906, 18700895, 25921077, 26892515, 34407635, 32423031, 35339733, 33391333, 33133164, 23375686, 25487149, 25647241, 9104431, 11196104, 11668640, 14974088, 20045108, 20663204, 21310417, 28104544, 28965616, 30592178, 29531935, 31447099, 20538126, 32015373, 32629184, 32695144, 32041611, 33303402, 32331935, 33740630, 33418990, 34037665, 34456049, 35913489, 33955087, 33994402, 25378237) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2020	PS4, PM1, PM2, PS3_Moderate, PP3 -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2016	Variant summary: The LDLR c.1246C>T (p.Arg416Trp) variant (alternatively also known as R395W) is located in the six-bladed beta-propeller, TolB-like domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. Functional analyses conclude that this variant results in defective LDLR recycling (Etxebarria_2015). The variant is widely reported as a pathogenic variant in literature found across many countries (Schmidt_2000, Real_2003, Leren_2004, Charng_2006, Humphries_2006, Tichy_2012). Other missense changes at this codon, namely p.Arg416Leu, p.Arg416Pro and p.Arg416Gln have been associated with FH, supporting that the codon is likely to be a mutational hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. This variant was found in 3/120616 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The heterozygotes in ExAC are likely to represent as subclinical cases or reduced penetrance as it is recurrently found mutation in FH patients. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 27, 2023	This missense variant (also known as p.Arg395Trp in the mature protein) replaces arginine with tryptophan at codon 416 in the LDLR type B repeat of the EGF precursor homology domain of the LDLR 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). A functional study has shown that this variant decreases LDLR cell surface expression and LDL uptake, and causes defective LDLR recycling due to protein degradation in lysosomes (PMID 25378237). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515, 27784735, 28104544, 32423031, 33740630, 33955087, 33994402, 34037665, 34407635, 34834584, 36499307). It has been shown that this variant segregates with hypercholesterolemia in multiple Norwegian families (PMID: 9104431). This variant has been identified in 6/251158 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg416Gln, is considered to be disease-causing (ClinVar variation ID: 251752), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 416 of the LDLR protein (p.Arg416Trp). This variant is present in population databases (rs570942190, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515). This variant is also known as p.Arg395Trp. ClinVar contains an entry for this variant (Variation ID: 183110). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25378237, 25647241). This variant disrupts the p.Arg416 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20045108, 20538126), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 03, 2019

The p.Arg416Trp variant in LDLR has been reported in >30 individuals with familial hypercholesterolemia (FH) and segregated with disease in 1 affected relative (Day 1997, DuÅ¡kovÃ¡ 2011, TichÃ½ 2012, Bertolini 2013, Do 2015, Etxebarria 2015, Han 2015, SÃ¡nchez-HernÃ¡ndez 2016, Sharifi 2016, Durst 2017). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 183110) and been identified in 3/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs570942190). This frequency is low enough to be consistent with the frequency of FH in the general population. Amino acid position 416 is a known mutation hotspot, with many other variants (p.Arg416Pro, p.Arg416Leu and p.Arg416Gln) reported in individuals with FH (Liguori 2001, Bertolini 2013, Chiou 2010, Thiart 1998, Huijgen 2012). Functional studies provide some evidence that the p.Arg416Trp variant may impact protein function (Etxebarria 2015). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, low frequency in the general population, functional and computational evidence and its presence in a known mutational hotspot. The ACMG/AMP criteria applied: PS4, PM1, PM2, PS3_Moderate, PP3 (Richards 2015). -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2022

The p.R416W pathogenic mutation (also known as c.1246C>T), located in coding exon 9 of the LDLR gene, results from a C to T substitution at nucleotide position 1246. The arginine at codon 416 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, also known as R395W, has been described in a number of hypercholesterolemic individuals worldwide, and has been reported to segregate with the disease in several families (Day IN et al. Hum. Mutat., 1997;10:116-27; Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Schmidt H et al. Atherosclerosis, 2000 Feb;148:431-2; Weiss N et al. J. Inherit. Metab. Dis., 2000 Dec;23:778-90; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; García-García AB et al. Hum. Mutat., 2001 Nov;18:458-9; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Goldmann R et al. BMC Med. Genet., 2010 Jul;11:115; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Han Y et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jul;79:1148-51; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). In addition, functional studies have indicated this alteration would affect protein recycling, causing reduced LDLR membrane expression and thus reduced ligand uptake (Etxebarria A et al. Hum. Mutat., 2015 Jan;36:129-41). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.34

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.2

M;.;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.8

D;D;D;D;D;D

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.72

MutPred

0.86

Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);.;.;.;Loss of disorder (P = 0.0075);

MVP

1.0

MPC

0.82

ClinPred

0.79

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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