19-11116936-C-T

Position:

chr19-11116936-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3PP4PS4PP1_Strong

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) 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: PS4 - Variant meets PM2. Variant identified in 12 index cases.PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology.PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023581/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

12

4

3

Clinical Significance

Pathogenic reviewed by expert panel P:20U:5

Conservation

PhyloP100: 0.487

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 Pathogenic. Variant got 12 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.

PP1

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.1783C>T	p.Arg595Trp	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.1783C>T	p.Arg595Trp	missense_variant	12/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152058

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251488

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135918

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:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

22

AN:

1461856

Hom.:

0

Cov.:

34

AF XY:

0.0000151

AC XY:

11

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152058

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:11Uncertain:4

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 09, 2024	This missense variant (also known as p.Arg574Trp in the mature protein) replaces arginine with tryptophan at codon 595 in the fifth LDLR type B repeat of the EGF precursor homology domain 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 over 20 individuals affected with familial hypercholesterolemia (PMID: 11737238, 16250003, 20538126, 25461735, 28502510, 32044282, 32331935, 34037665, 34176852; Color internal data), including three homozygous individuals with severe phenotype (PMID: 27784735). This variant has been identified in 2/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg595Leu and Arg595Gln) have been reported in individuals affected with familial hypercholesterolemia (ClinVar variation ID: 252029, 183126), suggesting that arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 09, 2021	NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) 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: PS4 - Variant meets PM2. Variant identified in 12 index cases. PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology. PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx). -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 07, 2021	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 27, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 27, 2022	- -
Likely pathogenic, 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	- -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Familial hypercholesterolemia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.1783C>T;p.(Arg595Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 161290; PMID: 11737238; 25461735; 27784735; 16250003; 20538126) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ldl_recept_b) - PM1. The variant is present at low allele frequencies population databases (rs373371572 - gnomAD 0.0002631%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 252029 - c.1784G>T;p.(Arg595Leu)) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 11737238; 16250003; 20538126) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 595 of the LDLR protein (p.Arg595Trp). This variant is present in population databases (rs373371572, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolaemia (PMID: 11737238, 16250003, 20538126, 25461735, 27784735). ClinVar contains an entry for this variant (Variation ID: 161290). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Arg595 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15256764, 15359125, 16250003, 18718593, 25437892, 25487149, 27497240, 28502510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2019	Variant summary: LDLR c.1783C>T (p.Arg595Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes. c.1783C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia in the homozygous and compound heterozygous state (Mozas_2004, Junyent_2010, Damgaard_2005, Chiou_2012, Pek_2018, Pirillo_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, three as VUS, six as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 12, 2021	The c.1783C>T (p.Arg595Trp) variant, also known as p.Arg574Trp in LDLR gene that encodes for low density lipoprotein receptor, has been identified in several unrelated individuals (>10) who fulfill the clinical criteria of familial hypercholesterolemia and segregated with disease in ten informative meioses (PMID:11737238, 16250003, 20538126, 25461735, 28502510). In-silico computational prediction tools suggest that the p.Arg595Trp variant may have deleterious effect on the protein function (REVEL score: 0.89). This variant is found to be rare (2/282862 chromosomes) in the general population database, gnomAD. This variant is interpreted as pathogenic by multiple submitters in the ClinVar database including the ClinGen expert panel (ClinVar ID: 161290). Another amino acid substitution at same position (p.Arg595Gln) has been classified as pathogenic by the ClinGen expert panel (ClinVar ID:183126). Therefore, the c.1783C>T (p.Arg595Trp) variant in LDLR gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2023	This missense variant (also known as p.Arg574Trp in the mature protein) replaces arginine with tryptophan at codon 595 in the fifth LDLR type B repeat of the EGF precursor homology domain 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 over 20 individuals affected with familial hypercholesterolemia (PMID: 11737238, 16250003, 20538126, 25461735, 28502510, 32044282, 32331935, 34037665, 34176852; Color internal data), including three homozygous individuals with severe phenotype (PMID: 27784735). This variant has been identified in 2/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg595Leu and Arg595Gln) have been reported in individuals affected with familial hypercholesterolemia (ClinVar variation ID: 252029, 183126), suggesting that arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a pathogenic variant by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar Variant ID#171218; SCV001960931.1); Also known as p.(R574W); This variant is associated with the following publications: (PMID: 25637381, 28502510, 29172679, 28965616, 15823288, 16250003, 28502495, 30586733, 31491741, 31447099, 33740630, 34037665, 29353225, 32331935, 11737238, 15241806, 27578128, 30583242, 34906454, 34526433, 33994402, 34176852, 20538126, 25461735, 27784735) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2017	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.1783C>T (p.R595W) alteration is located in coding exon 12 of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1783, causing the arginine (R) at amino acid position 595 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/282862) total alleles studied. The highest observed frequency was 0.002% (2/129168) of European (non-Finnish) alleles. This variant has been reported in several individuals with familial hypercholesterolemia (FH) from varying ethnic backgrounds (Descamps, 2001; Damgaard, 2005; Tejedor, 2005; Fouchier, 2005; Chiou, 2010; Jannes, 2015; Bañares, 2017; Pirillo, 2017; Pek, 2018). Another alteration at the same codon, p.R595Q (c.1784G>A), has also been detected in individuals with FH (Fouchier, 2005). This amino acid position is highly conserved in available vertebrate species. Functional studies of this variant demonstrated reduced binding capacity and receptor recycling (Guo, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Hypercholesterolemia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.52

D

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

26

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.73

D

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Pathogenic

0.87

D

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

4.0

H;.;.;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.52

T

PROVEAN

Pathogenic

-7.9

D;D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.93

MVP

1.0

MPC

0.82

ClinPred

1.0

D

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

Other links and lift over

dbSNP: rs373371572; hg19: chr19-11227612; COSMIC: COSV52943364; COSMIC: COSV52943364;