rs11669576

chr19-11111624-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):c.1171G>A(p.Ala391Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,613,444 control chromosomes in the GnomAD database, including 2,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A391P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.080 (764 hom., cov: 31)
  • Exomes 𝑓: 0.048 (2184 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Benign reviewed by expert panel B:23 O:1
• Conservation: PhyloP100: -0.270

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 -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000527.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034609437).
• BP6: Variant 19-11111624-G-A is Benign according to our data. Variant chr19-11111624-G-A is described in ClinVar as [Benign]. Clinvar id is 183138.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11111624-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1171G>A	p.Ala391Thr	missense_variant	8/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1171G>A	p.Ala391Thr	missense_variant	8/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12192 AN: 152174 Hom.: 765 Cov.: 31

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.0583

GnomAD3 exomes AF: 0.0434 AC: 10892 AN: 250704 Hom.: 450 AF XY: 0.0408 AC XY: 5527 AN XY: 135630

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0487

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0475 AC: 69434 AN: 1461152 Hom.: 2184 Cov.: 32 AF XY: 0.0460 AC XY: 33454 AN XY: 726870

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.0287

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00527

Gnomad4 FIN exome AF: 0.0451

Gnomad4 NFE exome AF: 0.0496

Gnomad4 OTH exome AF: 0.0512

GnomAD4 genome AF: 0.0801 AC: 12198 AN: 152292 Hom.: 764 Cov.: 31 AF XY: 0.0761 AC XY: 5669 AN XY: 74454

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.0437

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.0449

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0504 Hom.: 480

Bravo AF: 0.0855

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.173 AC: 762

ESP6500EA AF: 0.0484 AC: 416

ExAC AF: 0.0464 AC: 5631

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0499

ClinVar

Significance: Benign

Submissions summary: Benign:23 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:13

Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Mar 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	DLCN criteria >=3. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jul 23, 2018	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as likely benign. -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 23, 2021	The NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr) 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 = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5% BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals, as well as in homozygosity in 58 normolipidemic individuals. BP2 - Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype. BP4 - REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT. -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	MAF = 0.10 in normolipidemic controls; MAF = 8,7% in 86 Spanish healthy individuals; 0/200 Brazilian (european ancestry) normolipidemic individuals; 0/100 healthy control individuals; 0/77 healthy control individuals -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
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, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
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	subjects mutated among 2600 FH index cases screened = 201 6 being homozygotes / Software predictions: Benign -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2017	- -

Familial hypercholesterolemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 30, 2019	- -

not provided Benign:1 Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	5.0
Dann	Benign	0.22
DEOGEN2	Uncertain	0.45	T;.;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.83	T;T;T;T;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.1	N;.;.;.;.;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.68	N;N;N;N;N;N
Sift	Benign	0.57	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0050	B;.;.;.;.;.
Vest4		0.019
MPC		0.24
ClinPred		0.0040	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11669576; hg19: chr19-11222300; COSMIC: COSV52943212; COSMIC: COSV52943212;