19-11111506-T-C

Position:

• chr19-11111506-T-C

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1061-8T>C 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/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:BA1: PopMax FAF = 0.008564 in African/African American population in gnomAD (gnomAD v2.2.1).BS3_Supporting: Heterozygous patient cells were used for RNA assays (Level 3 experiment) shown normal LDLR transcripts reported from 2 research labs: Bourbon et al, Unidade de Investigacao Cardiovascular, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, (PMID 19411563); Holla et al, Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway, (PMID 19208450). Functional studies is consistent with no damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023412/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0069 (48 hom.)
• Consequence: LDLR ENST00000558518.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000006032
• Clinical Significance: Benign reviewed by expert panel U:1 B:24
• Conservation: PhyloP100: -0.0370

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.1061-8T>C		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.1061-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 968 AN: 152188 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00728

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00548 AC: 1376 AN: 251058 Hom.: 6 AF XY: 0.00546 AC XY: 741 AN XY: 135772

Gnomad AFR exome AF: 0.00823

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00691 AC: 10094 AN: 1460636 Hom.: 48 Cov.: 31 AF XY: 0.00689 AC XY: 5010 AN XY: 726662

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.00379

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.00772

Gnomad4 OTH exome AF: 0.00698

GnomAD4 genome AF: 0.00638 AC: 972 AN: 152306 Hom.: 3 Cov.: 31 AF XY: 0.00611 AC XY: 455 AN XY: 74482

Gnomad4 AFR AF: 0.00830

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00728

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00681 Hom.: 6

Bravo AF: 0.00667

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00818

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:12

Benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 25, 2022	The NM_000527.5 (LDLR):c.1061-8T>C 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/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BA1: PopMax FAF = 0.008564 in African/African American population in gnomAD (gnomAD v2.2.1). BS3_Supporting: Heterozygous patient cells were used for RNA assays (Level 3 experiment) shown normal LDLR transcripts reported from 2 research labs: Bourbon et al, Unidade de Investigacao Cardiovascular, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, (PMID 19411563); Holla et al, Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway, (PMID 19208450). Functional studies is consistent with no damaging effect. -
Benign, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 12, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	MAF =<0.3% -
Benign, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 17, 2015	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	2/75 Portuguese normolipidemic individuals -

not specified Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LDLR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2022	- -

Familial hypercholesterolemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	-	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 19, 2022	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2018

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	-0.84
CADD	Benign	1.6
DANN	Benign	0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000060
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: rs72658861; hg19: chr19-11222182;