rs72658860

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PP3PP1BS2BA1BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.970G>A (p.Gly324Ser) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP2, PP1 and PP3) 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: BA1 - FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). BS2 - Identified in 4 heterozygous non-affected family members from different labs.BP2 - variant identified 1 index case with heterozygous FH phenotype who is double heterozygous with NM_000384.3(APOB):c.10580G>A p.Arg3527Gln (ClinVar ID 17890) - classified as Pathogenic by the general ACMG guidelines (Chora et al., 2018).PP1 - variant segregates with phenotype in 2 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PP3 - REVEL = 0.815.Variant has 1 stand alone, 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Benign, and only 2 Supporting codes 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/CA023801/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0038 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 3 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:2U:3B:18O:1

Conservation

PhyloP100: 6.61

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 Benign. Variant got -11 ACMG points.

PP1

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

PP3

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.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.970G>A	p.Gly324Ser	missense_variant	Exon 7 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.970G>A	p.Gly324Ser	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000919

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:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000881

AC:

221

AN:

250886

Hom.:

AF XY:

0.000619

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.000289

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000343

AC:

502

AN:

1461590

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

201

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0132

Gnomad4 AMR exome

AF:

0.000358

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:

0.00000360

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152242

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.000918

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000824

Hom.:

Bravo

AF:

0.00407

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00115

AC:

140

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Uncertain:3Benign:18Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:3Benign:5

Feb 13, 2019

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 2 / Software predictions: Damaging -

Mar 01, 2016

Iberoamerican FH Network

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: flagged submission

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

Reevaluation of the ACMG criteria for this entry: PP3, PS4, PP1, BS2 and BP2 can be scored. Therefore the classification is for Uncertain significance. -

May 23, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 23, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.970G>A (p.Gly324Ser) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP2, PP1 and PP3) 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: BA1 - FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). BS2 - Identified in 4 heterozygous non-affected family members from different labs. BP2 - variant identified 1 index case with heterozygous FH phenotype who is double heterozygous with NM_000384.3(APOB):c.10580G>A p.Arg3527Gln (ClinVar ID 17890) - classified as Pathogenic by the general ACMG guidelines (Chora et al., 2018). PP1 - variant segregates with phenotype in 2 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL = 0.815. Variant has 1 stand alone, 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Benign, and only 2 Supporting codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4Other:1

Jun 13, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32719484, 20981092, 12436241, 11810272, 21722902, 11435110, 9544746, 25647241, 26332594, 25487149, 25637381, 22995991) -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Familial hypercholesterolemia

Benign:4

Apr 03, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 29, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Apr 05, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.970G>A (p.Gly324Ser) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 282414 control chromosomes, predominantly at a frequency of 0.014 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Co-occurrences with other pathogenic LDLR variants have been reported (LDLR c.862G>A, p.E288K; LDLR c.1285G>A, p.Val429Met; internal data and Vaca_2011), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 13 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely pathogenic (n=1), pathogenic (n=1), likely benign (n=4) and benign (n=5). Based on the evidence outlined above, the variant was classified as benign. -

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 1.3% in African chromosomes - disease prevalence is 1/200-1/300, occurs at greater freq than expected for disorder. It is classified in ClinVar with 1 star as both Likely pathogenic and Likely benign. It has been reported in 6 publications in HGMD but most suggest that it is not pathogenic. -

May 18, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia

Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype

Benign:1

May 31, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

0.16

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

MetaRNN

Benign

0.031

T;T;T;T;T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.8

M;.;.;.;.;M

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-5.8

D;D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Benign

0.041

D;D;D;D;D;D

Sift4G

Uncertain

0.036

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.55

MVP

1.0

MPC

0.31

ClinPred

0.15

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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