rs72658867

Positions:

• chr19-11120527-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.2140+5G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS3_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: BA1 - FAF = 0.01030 (1.030%) in European non-Finnish exomes (gnomAD v2.1.1). BS3_supporting - Level 3 assay: PMID:19208450 - study on patient's lymphocytes, Northern blot + real-time PCR + FACS used: normal mRNA processing + 108% low-density lipoprotein receptor activity. ---- functional study is consistent with no damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023645/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0075 (7 hom., cov: 32)
  • Exomes 𝑓: 0.010 (113 hom.)
• Consequence: LDLR ENST00000558518.6 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Benign reviewed by expert panel U:1 B:24
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BS3: 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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2140+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2140+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.00751 AC: 1143 AN: 152188 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00736 AC: 1840 AN: 249922 Hom.: 14 AF XY: 0.00705 AC XY: 953 AN XY: 135254

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.0306

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.00127

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00981

GnomAD4 exome AF: 0.0104 AC: 15130 AN: 1460600 Hom.: 113 Cov.: 35 AF XY: 0.0101 AC XY: 7352 AN XY: 726658

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.00134

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00990

GnomAD4 genome AF: 0.00750 AC: 1142 AN: 152306 Hom.: 7 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74464

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.0300

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.0110 Hom.: 6

Bravo AF: 0.00750

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:12

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	19/745 healthy individuals; 1/75 normolipidemic portuguese controls -
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	subject mutated among 2600 FH index cases screened = 1/Polymorphisme cf whitall et al J Med Genet, 2002 -
Likely benign, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Likely benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 18, 2021	NM_000527.5(LDLR):c.2140+5G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS3_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: BA1 - FAF = 0.01030 (1.030%) in European non-Finnish exomes (gnomAD v2.1.1). BS3_supporting - Level 3 assay: PMID:19208450 - study on patient's lymphocytes, Northern blot + real-time PCR + FACS used: normal mRNA processing + 108% low-density lipoprotein receptor activity. ---- functional study is consistent with no damaging effect. -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	MAF =<0.3% -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 22, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LDLR: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial hypercholesterolemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 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. -

LDLR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 30, 2023

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2021

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	-0.73
CADD	Uncertain	24
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs72658867; hg19: chr19-11231203;