rs17248882

Variant names:

• chr19-11116849-G-A
• rs17248882
• NM_000527.5:c.1706-10G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. BS1 PP1_Moderate BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1706-10G>A variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS3_supporting and PP1_moderate as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BS1 - FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met.BS3_supporting - 2 Level 3 assays: PMID:25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing.PMID:19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells.---- Aberrant transcripts are not detected, so BS3_Supporting is Met.PP1_moderate - Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met.Variant has 1 Strong plus 1 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence code towards Pathogenic, not enough for Likely pathogenic, so we are confident in classifying this variant as Likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA035940/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (8 hom.)
• Consequence: LDLR NM_000527.5 intron
• Scores: Splicing: ADA: 0.001607
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:27
• Conservation: PhyloP100: -0.240
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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	c.1706-10G>A		intron_variant	Intron 11 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1706-10G>A		intron_variant	Intron 11 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152182 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00232 AC: 584 AN: 251472 AF XY: 0.00247

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00199 AC: 2901 AN: 1461206 Hom.: 8 Cov.: 34 AF XY: 0.00204 AC XY: 1481 AN XY: 726904

African (AFR) AF: 0.000388 AC: 13 AN: 33468

American (AMR) AF: 0.00344 AC: 154 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00276 AC: 238 AN: 86210

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53394

Middle Eastern (MID) AF: 0.0127 AC: 67 AN: 5294

European-Non Finnish (NFE) AF: 0.00192 AC: 2131 AN: 1111952

Other (OTH) AF: 0.00265 AC: 160 AN: 60336

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74476

African (AFR) AF: 0.000192 AC: 8 AN: 41562

American (AMR) AF: 0.00301 AC: 46 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00225 AC: 153 AN: 68036

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00185

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3 Benign:27

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:3 Benign:13

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 = 15 -

Mar 01, 2016

Iberoamerican FH Network

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

1/125 non-FH individuals -

Mar 30, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 28, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. 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. -

Aug 31, 2016

Cardiovascular Biomarker Research Laboratory, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

MAF =<0.3%, LDL-C >=160 mg/dL -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 02, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Mar 16, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.1706-10G>A variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS3_supporting and PP1_moderate as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BS1 - FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met. BS3_supporting - 2 Level 3 assays: PMID: 25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing. PMID: 19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells. ---- Aberrant transcripts are not detected, so BS3_Supporting is Met. PP1_moderate - Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met. Variant has 1 Strong plus 1 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence code towards Pathogenic, not enough for Likely pathogenic, so we are confident in classifying this variant as Likely benign. -

Apr 02, 2015

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:5

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 26, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: BP4, BS1 -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

Feb 03, 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 is an intronic variant in LDLR. It is classified as DM? in HGMD. It has been reported in 2 probands with hypercholesterolemia but in both co-occurred with another variant. It is classified in ClinVar with 1 star as Benign by Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital, Likely benign by British Heart Foundation and Instituto Nacional de Saude Doutor Ricardo Jorge (in 1/125 non-FH individuals), and as VUS by CHOP. It has a max MAF in ExAC of 0.38% (44 Latino alleles) and in gnomAD of 0.4% (41 Ashkenazi and 122 Latino alleles). -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 04, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:4

Jan 19, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Sep 28, 2021

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
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.74
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17248882; hg19: chr19-11227525;