rs143992984

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. BS2BP2PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.806G>A (p.Gly269Asp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BP2 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 - Identified in 7 heterozygous controls from ABraOM database, and 2 non-affected family members from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 - variant identified in 2 Index cases with heterozygous FH phenotype and a 2nd LDLR variant classified as Pathogenic by these guidelines.PP1_moderate - variant segregates with phenotype in 5 informative meiosis in 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely 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 Likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023767/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:2U:3B:14O:1

Conservation

PhyloP100: 2.44

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_benign. Variant got -3 ACMG points.

PP1

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

BP2

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

BS2

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.806G>A	p.Gly269Asp	missense_variant	5/18	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.806G>A	p.Gly269Asp	missense_variant	5/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000176

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000239

AC:

AN:

251476

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000164

AC:

240

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000282

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0000840

Hom.:

Bravo

AF:

0.000404

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:2Uncertain:3Benign:14Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:1Benign:8

Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely benign, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, no assertion criteria provided	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.806G>A (p.Gly269Asp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BP2 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 - Identified in 7 heterozygous controls from ABraOM database, and 2 non-affected family members from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 - variant identified in 2 Index cases with heterozygous FH phenotype and a 2nd LDLR variant classified as Pathogenic by these guidelines. PP1_moderate - variant segregates with phenotype in 5 informative meiosis in 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely 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 Likely benign. -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2015	MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 08, 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. -
Likely benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, 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	subjects mutated among 2600 FH index cases screened = 3 / FH-Rome-3 / Software predictions: Conflicting -
Likely benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/212 non-FH alleles -

not provided

Uncertain:1Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2016	Variant summary: c.806G>A affects a non-conserved nucleotide, resulting in amino acid change from Gly to Asp. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). Functional study showed that the LDL uptake, binding capacity of LDL, and LDLR expression of variant were similar to those observed in control cells (Etxebarria_2012), indicating the neutral effect. This variant was found in 24/131566 control chromosomes at a frequency of 0.0001824. This variant has been reported in multiple FH patients without strong evidence for causality. Among the reported patients, variant was reported to co-occur with a deleterious LDLR variant c.1045delC in cis (Mozas_2004) and there is at least one family reported with lack of co-segregation of this variant with disease (Bourbon_2008). In addition, variant has been detected in early-onset myocardial infarction case with comparable allele frequency as in controls and multiple publications listed variant as nonpathogenic/benign (Do_2015, Etxebarre_2012, and Benito-Vicente_2015). Considering all, this variant is classified as Benign. -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2024	Identified in patients with hypercholesterolemia and acute MI in published literature (PMID: 17765246, 25606447, 25741862, 36555767, 33740630, 35339733, 26332594, 15241806, 25487149, 23375686); however this variant was also observed in individuals with normal cholesterol levels and the variant did not segregate with disease in at least one family reported; Published functional studies suggest the p.(G269D) results in LDLR activity and expression and LDL uptake similar to wildtype (PMID: 21990180, 25647241); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G248D) and FH Rome-3; This variant is associated with the following publications: (PMID: 21990180, 15241806, 25647241, 26332594, 23375686, 25637381, 25487149, 32719484, 33740630, 36555767, 25741862, 25606447, 35339733, 17765246, 28145427) -

Familial hypercholesterolemia

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 10, 2018	- -

Hypercholesterolemia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2019

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

Benign

0.099

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

D;.;.;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.11

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

-0.31

N;.;.;.;N

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.5

D;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Benign

0.33

T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.0090

B;.;.;.;.

Vest4

0.50

MVP

1.0

MPC

0.40

ClinPred

0.088

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.57

gMVP

0.87

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