rs116405216

Positions:

• chr19-11110648-G-A
• chr19-11110648-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.941-4G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP4) 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:BA1 - FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1).BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in more than 100 non-FH patients from Ambry Genetics.BP4 - No REVEL, splicing evaluation needed.Functional data on splicing not available.A) variant located at -20 to +3 bases from canonical acceptor splice siteMES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64.Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not above 1.0B) variant is intronicC) variant is intronicVariant is not predicted to alter splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA030790/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0076 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (9 hom.)
• Consequence: LDLR NM_000527.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003096
• Clinical Significance: Benign reviewed by expert panel P:1 U:2 B:16
• Conservation: PhyloP100: -0.336

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 -13 ACMG points.

• BP4: 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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.941-4G>A		splice_region_variant, splice_polypyrimidine_tract_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.941-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1147 AN: 152118 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000588

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00193 AC: 485 AN: 250890 Hom.: 4 AF XY: 0.00141 AC XY: 192 AN XY: 135718

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00127

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: 0.0000353

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000768 AC: 1122 AN: 1461238 Hom.: 9 Cov.: 31 AF XY: 0.000645 AC XY: 469 AN XY: 726908

Gnomad4 AFR exome AF: 0.0268

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00765 AC: 1164 AN: 152236 Hom.: 15 Cov.: 32 AF XY: 0.00687 AC XY: 511 AN XY: 74434

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00488 Hom.: 2

Bravo AF: 0.00827

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 30, 2015	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 20, 2023	The NM_000527.5(LDLR):c.941-4G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP4) 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: BA1 - FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1). BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in more than 100 non-FH patients from Ambry Genetics. BP4 - No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located at -20 to +3 bases from canonical acceptor splice site MES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64. Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not above 1.0 B) variant is intronic C) variant is intronic Variant is not predicted to alter splicing. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	MAF =<0.3%, likely pathogenic based on the integrative in-silico score -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	This variant is associated with the following publications: (PMID: 28145427, 23680767, 10422804, 27884173, 26332594, 27765764, 16250003, 27044878) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 09, 2020	- -

Familial hypercholesterolemia Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	-	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 06, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

May 17, 2017

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2014

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	-0.81
CADD	Benign	0.080
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs116405216; hg19: chr19-11221324;