chr19-11110781-G-C

Position:

• chr19-11110781-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BA1 BP2 BP4 BS2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1060+10G>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 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 = 0.4446 (44.46%) in European non-Finnish exomes (gnomAD v2.1.1).BS2 - observed in homozygosity in 155 normolipidemic individuals (118 from Color, 22 from INSA, 15 from Western University), as well as in heterozygosity in 376 normolipidemic individuals (297 from Color, 46 INSA, 33 from Western University).BP2 - Variant co-occurs with a Pathogenic LDLR variant (classified by these guidelines) in 6 individuals with a clear heterozygous FH phenotype (LDL-C <8 mmol/L).BP4 - no REVEL, splicing evaluation required. No functional studies variant not on splicing limits, so BP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA031460/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.34 (10973 hom., cov: 32)
  • Exomes 𝑓: 0.44 (143674 hom.)
• Consequence: LDLR ENST00000558518.6 intron
• Clinical Significance: Benign reviewed by expert panel B:25
• Conservation: PhyloP100: -2.63

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 -14 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1060+10G>C		intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1060+10G>C		intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51905 AN: 151968 Hom.: 10986 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.397 AC: 99142 AN: 249942 Hom.: 21355 AF XY: 0.404 AC XY: 54676 AN XY: 135342

Gnomad AFR exome AF: 0.0836

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.389

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.448

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.436 AC: 636335 AN: 1459836 Hom.: 143674 Cov.: 45 AF XY: 0.435 AC XY: 316243 AN XY: 726342

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.463

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.416

GnomAD4 genome AF: 0.341 AC: 51882 AN: 152086 Hom.: 10973 Cov.: 32 AF XY: 0.345 AC XY: 25639 AN XY: 74342

Gnomad4 AFR AF: 0.0913

Gnomad4 AMR AF: 0.436

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.503

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.367

Alfa AF: 0.321 Hom.: 1476

Bravo AF: 0.324

Asia WGS AF: 0.268 AC: 934 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:25

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:10

Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	MAF =<0.3% -
Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jun 08, 2018	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 23, 2021	The NM_000527.5(LDLR):c.1060+10G>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 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 = 0.4446 (44.46%) in European non-Finnish exomes (gnomAD v2.1.1). BS2 - observed in homozygosity in 155 normolipidemic individuals (118 from Color, 22 from INSA, 15 from Western University), as well as in heterozygosity in 376 normolipidemic individuals (297 from Color, 46 INSA, 33 from Western University). BP2 - Variant co-occurs with a Pathogenic LDLR variant (classified by these guidelines) in 6 individuals with a clear heterozygous FH phenotype (LDL-C <8 mmol/L). BP4 - no REVEL, splicing evaluation required. No functional studies variant not on splicing limits, so BP4 is met. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	22 Hmz + 46 Htz / 95 non-FH individuals; MAF = 49,4% in 86 Spanish healthy individuals -

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2016	c.1060+10G>C in intron 7 of LDLR: This variant is not expected to have clinical significance because it has been identified in 38.5% (46591/121050) of total chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs12710260). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	Variant summary: LDLR c.1060+7_1060+10delinsCCCC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. A constituent SNV, c.1060+10G>C of the variant allele was found at a frequency of 0.39 in 281296 control chromosomes in the gnomAD database (v2.1.1), including 23526 homozygotes. The other constituent SNV of this variant allele, c.1060+7T>C was found at a frequency of 0.9999 in control chromosomes in the gnomAD database (v2.1.1), and therefore, near complete overlap of the c.1060+10G>C occurrences can be assumed. The observed frequency of the c.1060+10G>C variant is approximately 311.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1060+7_1060+10delinsCCCC in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Familial hypercholesterolemia Benign:4

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	-	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2016

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	0.017
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs12710260; hg19: chr19-11221457; COSMIC: COSV52946917; COSMIC: COSV52946917;