rs552422789

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PP4PS4_SupportingPM5PM2

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5, PP3, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006164 (0.006%) in African/African American (gnomAD v2.1.1). PM5 - Two other missense variants described in the same codon (accessed 19 August 2020): --- 1 variant classified as Pathogenic by these guidelines.PP3 - REVEL: 0,809. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling Simon-Broome criteria.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (PMID:10882754 - 1 case with Simon-Broome criteria; PMID:17094996 - 1 case with Simon-Broome criteria). LINK:https://erepo.genome.network/evrepo/ui/classification/CA033088/MONDO:0007750/013

Frequency

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

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

8

7

4

Clinical Significance

Likely pathogenic reviewed by expert panel P:12U:4

Conservation

PhyloP100: 4.32

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 Likely_pathogenic. Variant got 7 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1217G>A	p.Arg406Gln	missense_variant	9/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1217G>A	p.Arg406Gln	missense_variant	9/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

2

AN:

151998

Hom.:

0

Cov.:

29

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

4

AN:

251042

Hom.:

0

AF XY:

0.0000221

AC XY:

3

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

10

AN:

1461320

Hom.:

0

Cov.:

33

AF XY:

0.00000688

AC XY:

5

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152116

Hom.:

0

Cov.:

29

AF XY:

0.0000134

AC XY:

1

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000754

Hom.:

0

ExAC

AF:

0.0000165

AC:

2

Asia WGS

AF:

0.000289

AC:

1

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:7Uncertain:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 09, 2021	NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5, PP3, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006164 (0.006%) in African/African American (gnomAD v2.1.1). PM5 - Two other missense variants described in the same codon (accessed 19 August 2020): --- 1 variant classified as Pathogenic by these guidelines. PP3 - REVEL: 0,809. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling Simon-Broome criteria. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (PMID: 10882754 - 1 case with Simon-Broome criteria; PMID: 17094996 - 1 case with Simon-Broome criteria). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM5+PP3_Moderate+PS4_Moderate -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, 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	subject mutated among 2600 FH index cases screened = 1 , family members = 3 with unclear co-segregation / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 25, 2024	This missense variant replaces arginine with glutamine at codon 406 in LDLR type B repeat 1 in EGF precursor homology domain of the LDLR protein. This variant is also known as p.Arg385Gln in the mature 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). Splice site prediction tools suggest that this variant may create a new acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 10882754, 17094996, 23680767, 28008010, 29353225, 33418990, 34037665, 36499307, ClinVar SCV000503318.1). Different missense variants affecting the same codon, p.Arg406Trp and p.Arg406Pro, are considered to be disease-causing (ClinVar variation ID: 226351 and 226352), suggesting that arginine at this position is important for LDLR protein function. This variant has been identified in 4/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2022	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg406Gln variant in LDLR has been reported in at least 9 individuals (including 1 African individual) with Familial Hypercholesterolemia (PMID: 17094996, 10882754, 23680767, 28008010; Variation ID: 228798), and has been identified in 0.001593% (4/251042) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs552422789). 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 as a VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 228798). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional variants with a different amino acid change at the same position, p.Arg406Pro and p.Arg406Trp, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 226352, 226351). cDNA analysis of an individual with a synonymous variant in the same codon suggests that this region may be important for splicing (PMID: 18400033). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PS4_supporting, PP3 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2023	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; In silico analysis supports that this missense variant has a deleterious effect on splicing; Also known as R385Q; This variant is associated with the following publications: (PMID: 29353225, 34037665, 17094996, 28008010, 16466730, 33418990, 36499307, 10882754) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 18, 2024	The LDLR c.1217G>A (p.Arg406Gln) variant has been reported in the published literature in individuals affected with Familial hypercholesterolemia, with the prevalence in FH patients being increased compared with the prevalence in controls (PMIDs: 33418990 (2021), 29353225 (2018), 17094996 (2007), 10882754 (2000)). The frequency of this variant in the general population, 0.000016 (4/251042 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with 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. -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 406 of the LDLR protein (p.Arg406Gln). This variant is present in population databases (rs552422789, gnomAD 0.007%). This missense change has been observed in individuals with LDLR-related conditions (PMID: 10882754, 17094996, 28008010). ClinVar contains an entry for this variant (Variation ID: 228798). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg406 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8882879, 25461735, 26343872). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 26, 2023	This missense variant replaces arginine with glutamine at codon 406 in LDLR type B repeat 1 in EGF precursor homology domain of the LDLR protein. This variant is also known as p.Arg385Gln in the mature 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). Splice site prediction tools suggest that this variant may create a new acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 10882754, 17094996, 23680767, 28008010, 29353225, 33418990, 34037665, 36499307, ClinVar SCV000503318.1). Different missense variants affecting the same codon, p.Arg406Trp and p.Arg406Pro, are considered to be disease-causing (ClinVar variation ID: 226351 and 226352), suggesting that arginine at this position is important for LDLR protein function. This variant has been identified in 4/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2024

The p.R406Q variant (also known as c.1217G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1217. The arginine at codon 406 is replaced by glutamine, an amino acid with highly similar properties. This alteration, which is also known as p.R385Q, has been reported in individuals with familial hypercholesterolemia (FH), including in an individual with concerns for homozygous FH, who had an additional alteration in LDLR identified (Thiart R et al. J Med Genet, 2000 Jul;37:514-9; Durst R et al. Atherosclerosis, 2006 Dec;189:443-50; Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11; Abul-Husn NS et al. Science, 2016 Dec;354:[ePub ahead of print]; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116; Razman AZ et al. Int J Mol Sci, 2022 Nov;23:[ePub ahead of print]; 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2019

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg406Gln variant in LDLR has been reported in 4 individuals with hypercholesterolemia (Thiart 2000, Tosi 2007, Abul Husn 2016, Pek 2017). It has also been identified in 0.006% (1/16224) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 228798). Computational prediction tools and conservation analysis suggest that the p.Arg406Gln variant may impact the protein. In addition, splicing prediction tools predict this variant results in the generation of a novel 3' splice site. However, the results of these computational tools are not predictive enough to determine pathogenicity. An additional variant involving this codon (p.Arg406Trp) has been identified in individuals with hypercholesterolemia and is classified as pathogenic by this laboratory, suggesting variation at this site may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PM2_Supporting, PP3, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.16

D

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

35

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.70

D

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

D

MutationAssessor

Benign

1.6

L;.;.;.;.;L

PrimateAI

Benign

0.37

T

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.023

D;D;D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.27

MutPred

0.95

Gain of ubiquitination at K411 (P = 0.0975);Gain of ubiquitination at K411 (P = 0.0975);.;.;.;Gain of ubiquitination at K411 (P = 0.0975);

MVP

1.0

MPC

0.56

ClinPred

0.81

D

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.83

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.83

Position offset: 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: rs552422789; hg19: chr19-11223984;