chr19-11116874-G-T

Position:

chr19-11116874-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PS4_SupportingPP3PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS4_supporting and PP4) 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:PM2 - PopMax MAF = 0.0001848 (0.01848%) in European (Finnish) exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.937.PP4 - Variant meets PM2. Identified in 2 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome score possible/definite, after alternative causes of high cholesterol were excluded.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome criteria (possible/definite). LINK:https://erepo.genome.network/evrepo/ui/classification/CA036228/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:6

Conservation

PhyloP100: 8.01

Variant links:

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]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

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 linkuse as main transcript	c.1721G>T	p.Arg574Leu	missense_variant	12/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1721G>T	p.Arg574Leu	missense_variant	12/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251472

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg574Leu variant in LDLR has been reported in 1 Czech individual with Familial Hypercholesterolemia (PMID: 22698793), and has been identified in 0.01848% (4/21640) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs777188764). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 237867). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic variants causing a different amino acid change at the same position, p.Arg574Cys and p.Arg574His, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 183123, 251996). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PP3 (Richards 2015). -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 30, 2022	NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS4_supporting and PP4) 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: PM2 - PopMax MAF = 0.0001848 (0.01848%) in European (Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.937. PP4 - Variant meets PM2. Identified in 2 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome score possible/definite, after alternative causes of high cholesterol were excluded. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome criteria (possible/definite). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant (also known as p.Arg553Leu in the mature protein) replaces arginine with leucine at codon 574 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with familial hypercholesterolemia (PMID: 22698793; ClinVar SCV002506357.1). This variant has been identified in 4/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg574His and p.Arg574Cys, are considered to be disease-causing (ClinVar variation ID: 251996 and 183123), suggesting that arginine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

Familial hypercholesterolemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2016	In summary, this is a novel missense change with uncertain impact on protein function that has been reported in one patient. However, the clinical significance of this finding is still unknown. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in an individual affected with hypercholesterolemia. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 22698793). This variant is present in population databases (rs777188764, ExAC 0.02%). This sequence change replaces arginine with leucine at codon 574 of the LDLR protein (p.Arg574Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This missense variant (also known as p.Arg553Leu in the mature protein) replaces arginine with leucine at codon 574 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with familial hypercholesterolemia (PMID: 22698793; ClinVar SCV002506357.1). This variant has been identified in 4/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg574His and p.Arg574Cys, are considered to be disease-causing (ClinVar variation ID: 251996 and 183123), suggesting that arginine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;.;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-6.7

D;D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.90

MutPred

0.87

Loss of catalytic residue at R574 (P = 0.0384);Loss of catalytic residue at R574 (P = 0.0384);.;.;.;Loss of catalytic residue at R574 (P = 0.0384);

MVP

1.0

MPC

0.91

ClinPred

0.95

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over