rs147509697

Positions:

chr19-11089606-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PP1_ModerateBS3BS4BS2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) 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: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database.BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met.BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy.Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023728/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:6B:16O:1

Conservation

PhyloP100: 1.04

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:

LDLR-AS1 (HGNC:):

LDLR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP1

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

BS2

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

BS3

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

BS4

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 linkuse as main transcript	c.58G>A	p.Gly20Arg	missense_variant	1/18	ENST00000558518.6	NP_000518.1
LDLR-AS1	NR_163945.1 linkuse as main transcript	n.54C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.58G>A	p.Gly20Arg	missense_variant	1/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000743

AC:

182

AN:

245116

Hom.:

AF XY:

0.000838

AC XY:

112

AN XY:

133624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00243

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.000917

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.000423

AC:

617

AN:

1459798

Hom.:

Cov.:

AF XY:

0.000442

AC XY:

321

AN XY:

726128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000538

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.000965

Gnomad4 NFE exome

AF:

0.000401

Gnomad4 OTH exome

AF:

0.000548

GnomAD4 genome

AF:

0.000512

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000691

Hom.:

Bravo

AF:

0.000521

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000899

AC:

109

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00142

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:6Benign:16Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:5Benign:4

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	A functional analysis was previously published (PavlouÅ¡kovÃ¡ et al, 2016). This variant has no effect on LDLR protein function. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Nov 29, 2010	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Feb 19, 2016	MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 16, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/150 normolipidemic chromosomes -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) 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: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. -

Familial hypercholesterolemia

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Dec 11, 2023	- -

not provided

Benign:3Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LDLR: BS3:Supporting, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 24, 2021	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2020	Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Hypercholesterolemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

LDLR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

T;.;.;.;.;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.97

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

T;T;T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.0086

T;T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.7

L;.;L;L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.19

T;D;D;T;D;T

Sift4G

Benign

0.56

T;T;T;T;T;T

Polyphen

0.12

B;.;.;.;.;.

Vest4

0.13

MutPred

0.56

Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);

MVP

1.0

MPC

0.35

ClinPred

0.025

GERP RS

0.32

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.12

gMVP

0.72

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

Other links and lift over