19-11123264-G-A

Position:

• chr19-11123264-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. BP4 BP2 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BP4, BP2 and PS3_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:BP4 - REVEL score is 0.291. It is below 0.5, so splicing evaluation is required. Functional data on splicing is not available. A) Variant not on limits. B) Variant is exonic and within range, but it does not create a de novo AG or GT site. The variant is not predicted to alter splicing.BP2 - 2 individuals from Ambry Genetics: Patient 1 has LDLR p.Gln33* in trans. Phenotype LDL 111 mg/dl (on treatment); Patient 2 has LDLR p.Gly373Asp in trans. Phenotype = "high chol".PS3_supporting - level 3 assay (PMID:9409298) - Heterozygous patients' lymphoblasts, immunoblotting, I125-LDL assay: no precursor detectable, degradation of 125I-LDL = 73%.Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Supporting evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023651/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00096 (3 hom.)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:1 B:20 O:2
• Conservation: PhyloP100: -2.23

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 Likely_benign. Variant got -1 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.2231G>A	p.Arg744Gln	missense_variant	15/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2231G>A	p.Arg744Gln	missense_variant	15/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152084 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000855 AC: 215 AN: 251340 Hom.: 1 AF XY: 0.000942 AC XY: 128 AN XY: 135872

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000959 AC: 1402 AN: 1461766 Hom.: 3 Cov.: 31 AF XY: 0.000942 AC XY: 685 AN XY: 727196

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152200 Hom.: 0 Cov.: 30 AF XY: 0.000591 AC XY: 44 AN XY: 74414

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.000654

ExAC AF: 0.000815 AC: 99

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00142

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:20 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1 Benign:10

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Mar 23, 2017	- -
Likely 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%. -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -
Likely benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	May 27, 2022	The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BP4, BP2 and PS3_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: BP4 - REVEL score is 0.291. It is below 0.5, so splicing evaluation is required. Functional data on splicing is not available. A) Variant not on limits. B) Variant is exonic and within range, but it does not create a de novo AG or GT site. The variant is not predicted to alter splicing. BP2 - 2 individuals from Ambry Genetics: Patient 1 has LDLR p.Gln33* in trans. Phenotype LDL 111 mg/dl (on treatment); Patient 2 has LDLR p.Gly373Asp in trans. Phenotype = "high chol". PS3_supporting - level 3 assay (PMID: 9409298) - Heterozygous patients' lymphoblasts, immunoblotting, I125-LDL assay: no precursor detectable, degradation of 125I-LDL = 73%. Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Supporting evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely 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). 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely pathogenic, flagged submission	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -
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 = 7 / previously described in association with FH/Software predictions: Benign -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Dec 31, 2023	ACMG categories: BP1,BP4 -

not provided Benign:6 Other:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	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. -
not provided, no classification provided	literature only	SNPedia	-	- -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	LDLR: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2017	Variant summary: The LDLR c.2231G>A (p.Arg744Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is located outside of any known functional domain or repeat. 4/4 in silico tools predict benign outcome for this variant (SNP&GO was not used due to a low reliability index), however no experimental studies were published at the time of evaluation (ACMG BP4). The variant of interest has been identified in a large, broad control datasets of ExAC at a frequency of 0.0008 (99/121250 chrs tested), reaching the 0.0011 in several sub-populations (South Asians and European NF) including 1 homozygote. Although the observed frequency is similar to the estimated maximal expected allele frequency of a pathogenic LDLR variant (~0.001), thus supporting benign interpretation, the information on lipid profiling in these individuals is not available for individual review. The variant of interest was reported in multiple patients with elevated cholesterol level, including patient(s) carrying a known pathogenic variant APOB p.R3500Q (ACMG BP5), in whom lipid profiling results were not significantly different from data observed in patients carrying APOB R3500Q alone (Brusgaard, 2006) (ACMG BP5). In addition, per Dutch FH-database, cholesterol levels of R723Q positive and R723Q negative relatives are virtually similar (ACMG BS4), again favoring benign classification. The c.2231G>A was identified heterozygously in a healthy Caucasian adult undergoing carrier screening (ACMG BS2). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign (ACMG BP6). Considering all evidence the variant was conservatively classified as Likely Benign until additional evidence supporting its presence in normolipedimic control subjects is obtained.ACMG Classification: BRationale for Pathogenicity: none. Rationale for being Benign: BS2, BS4, BP4, BP5; BP6 was not engaged due to discordant classifications. -

Familial hypercholesterolemia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 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	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.042
DANN	Benign	0.70
DEOGEN2	Benign	0.36	T;.;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.42	T;T;T;T;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.024	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N;.;.;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.43	N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.60	T;T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.037
MVP		0.97
MPC		0.24
ClinPred		0.0012	T
GERP RS		-6.8
Varity_R		0.017
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137853963; hg19: chr19-11233940;