chr19-11105457-G-A

Position:

chr19-11105457-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.551G>A(p.Cys184Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C184R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:27O:1

Conservation

PhyloP100: 9.72

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 20 ACMG points.

PS1

Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a disulfide_bond (size 17) in uniprot entity LDLR_HUMAN there are 50 pathogenic changes around while only 1 benign (98%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11105456-T-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 19-11105457-G-A is Pathogenic according to our data. Variant chr19-11105457-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3739.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11105457-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.551G>A	p.Cys184Tyr	missense_variant	4/18	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.551G>A	p.Cys184Tyr	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152232

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727174

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:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

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:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:17

Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 25, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 22, 2019	- -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/100 healthy control individuals -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 30, 2019	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
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	subjects mutated among 2600 FH index cases screened = 2 /FH-Rome-2 / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 20, 2018	This c.551G>A (p.Cys184Tyr) variant in the LDLR gene has been reported to segregate with familial hypercholesterolemia in several families (PMID: 9678702) and has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID: 10559517, 11668627, 17765246, 20236128) and is rarely detected in the general population. Cysteine residue at position 184 of the LDLR protein is highly evolutionarily conserved. Based on this information, the c.551G>A (p.Cys184Tyr) variant in the LDLR gene is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2022	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 22, 2022	The NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM1, PS3, PS4, PP1_Strong, 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 = 0.00019 (0.019%) in European Non-Finnish genomes (gnomAD v2.1.1). PP3 - REVEL = 0.85, which is above the threshold of 0.75. PM1 - variant meets PM2 and is located in exon 4. PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: Result of normal cell surface LDLR (100%), 4% LDL binding and 18% LDL uptake, compared to wild-type (PMID: 34167030). PS4 - Variant meets PM2 and is identified in at least 22 unrelated index cases who fulfill clinical criteria for FH (8 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN criteria from Robarts Research Institute; 5 cases with DLCN criteria from PathWest Laboratory Medicine WA; 2 cases with DLCN criteria from Color; 1 case with MEDPED criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory). PP1_Strong - Variant segregates with phenotype in 14 informative meioses from 8 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 4 families: 8 relatives affected with the variant and 1 relative unaffected without the variant; Robarts Research Institute – 2 families: 2 relatives affected with the variant; PathWest Laboratory Medicine WA – 2 families: 2 affected relative with the variant and 1 unaffected relative without the variant) PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant (also known as p.Cys163Tyr in the mature protein) replaces cysteine with tyrosine at codon 184 in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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). A functional study in transfected CHO-ldlA7 cells has shown that this variant causes a significant reduction in LDL binding and uptake (PMID: 34167030). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (11668627, 19843101, 20236128, 20828696, 31345425, 32331935, 34037665, 34297352; Color internal data). It has been shown that this variant segregates with disease in over 10 affected individuals across 3 families (PMID: 9678702). This variant has been identified in 3/31402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys184Arg, is considered to be disease-causing (ClinVar variation ID: 251294), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Familial hypercholesterolemia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 12, 2023	This missense variant replaces cysteine with tyrosine at codon 184 in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Cys163Tyr in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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). A functional study has shown that this variant causes a significant reduction in LDL binding and uptake (PMID: 34167030). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 11668627, 19843101, 20236128, 20828696, 31345425, 32331935, 34037665, 34297352; Color internal data). It has been shown that this variant segregates with disease in over 10 affected individuals across 3 families (PMID: 9678702). This variant has been identified in 3/31402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys184Arg, is reported to be disease-causing (ClinVar variation ID: 251294), indicating that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 16, 2020	The c.551G>A variant in the LDLR gene replaces cysteine with tyrosine at codon 184 of the LDLR protein (p.Cys184Tyr). It has been reported to segregate with familial hypercholesterolemia in several families (PMID: 9678702) and has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID: 10559517, 11668627, 17765246, 20236128). This variant is observed at an ultra-low frequency in the general population (gnomAD database 3/31402) and reported to be damaging by multiple bioinformatics algorithms. This variant affects a cysteine residue located in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant was identified in a patient with familial hypercholesterolemia. Functional studies demonstrated reduced LDLR activity in fibroblasts derived from this patient. Based on this information, the c.551G>A (p.Cys184Tyr) variant in the LDLR gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 184 of the LDLR protein (p.Cys184Tyr). This variant is present in population databases (rs121908039, gnomAD 0.02%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9678702, 11668627, 20236128, 20828696, 25461735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys163Tyr. ClinVar contains an entry for this variant (Variation ID: 3739). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). 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	Jul 05, 2016	Variant summary: The LDLR c.551G>A (p.Cys184Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Cys184 is located in repeat 4 of the LDLR class A (cyteine-rich) repeat, and Cys184 is highly conserved across species. In LDL receptors, the class A domains form the binding site for LDL and calcium, and numerous familial hypercholestorolemia pathogenic LDLR variants alter the calcium coordinating residue of LDL-A domains.This variant was absent in 121144 control chromosomes, but has been cited in many FH families in the literature and has been shown to co-segregate with disease in multiple independent families (Lee_JMG_1998). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known FH-causing LDLR variant and was classified as Pathogenic. -

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 19, 2021	The LDLR c.551G>A; p.Cys184Tyr variant (rs121908039) is reported in the literature in 15 individuals affected with high LDL-C (Sturm 2021). Moreover, this variant has been identified as a recurrent co-segregating allele within three familial hypercholesterolemia families with ten informative meiosis cases (Lee 1998). This variant is also reported in ClinVar (Variation ID: 3739). This variant is found in the general population with an overall allele frequency of 0.0096% (3/31402 alleles) in the Genome Aggregation Database. The cysteine at codon 184 is highly conserved, is involved in disulfide bond formation of LDLR, and computational analyses predict that this variant is deleterious (REVEL: 0.854). Based on available information, this variant is considered to be pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies show that LDL-deficient CHO-ldlA7 cells transfected with the p.(C184Y)-LDL demonstrates impaired binding activity (PMID: 34167030); Also reported as FH Rome-2 and p.(C163Y) due to alternate nomenclature; This variant is associated with the following publications: (PMID: 31447099, 30586733, 9678702, 10559517, 11668627, 11810272, 20236128, 20828696, 25461735, 28873201, 33303402, 32719484, 32331935, 33740630, 33418990, 34037665, 27765764, 34363016, 22883975, 1301956, 32041611, 27680772, 31345425, 34297352, 24627126, 30583242, 34906454, 34167030) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 17, 2020	The variant has been reported in multiple families affected with familial hypercholesterolemia in the published literature (PMID: 24627126 (2014), 25461735 (2015), 27680772 (2016), 27765764 (2016), 31345425 (2019), 32331935 (2020)) as well as in individuals with early-onset myocardial infarction (PMID: 30586733 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. A different variant affecting the same amino acid position has been described as pathogenic. Based on the available information, the variant is predicted to be likely pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 11-12-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 03, 2019

The p.Cys184Tyr variant in LDLR (also described as p.Cys163Tyr in the literature) has been reported in >15 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 11 affected relatives from 4 families (Lee 1998, Graham 1999, Fouchier 2001, Wang 2001, Bourbon 2008, Jannes 2015, Martin 2016). It has also been reported by other clinical laboratories in ClinVar (Variation ID 3739). This variant has been identified in 3/15004 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs121908039). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Cys184Tyr variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, very low frequency in the general population and computational evidence. The ACMG/AMP Criteria applied (Richards 2015): PS4, PP1_Strong, PM2, PP3. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2022

The c.551G>A (p.C184Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 551, causing the cysteine (C) at amino acid position 184 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (3/31402) total alleles studied. The highest observed frequency was 0.02% (3/15432) of European (non-Finnish) alleles. This variant has been described in numerous familial hypercholesterolemia (FH) cohorts (Hobbs, 1992; Graham, 1999; Hooper, 2012; Taylor, 2010; Wang, 2016). In one study, this variant was observed to co-segregate with FH in multiple relatives from three families (Lee, 1998). Another alteration at the same codon, p.C184R (c.550T>C), has also been described in patients with FH (Pimstone, 1998). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 4 (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.98

D;.;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.72

T;T;T;T

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.0

H;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-9.6

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.97

MutPred

0.85

Loss of disorder (P = 0.086);Loss of disorder (P = 0.086);.;Loss of disorder (P = 0.086);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.98

gMVP

1.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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