rs577934998

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.664T>C(p.Cys222Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,610,504 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C222F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:15U:1

Conservation

PhyloP100: 7.92

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 18 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain 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 chr19-11105571-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251362.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 19-11105570-T-C is Pathogenic according to our data. Variant chr19-11105570-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226332.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11105570-T-C is described in Lovd as [Pathogenic]. Variant chr19-11105570-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.664T>C	p.Cys222Arg	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.664T>C	p.Cys222Arg	missense_variant	4/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151930

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249776

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458458

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:10Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces cysteine with arginine at codon 222 in the LDLR type A repeat 5 of the LDLR protein. This variant is also known as p.Cys201Arg 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 10532689, 15823276, 15823288, 22883975, 25043216, 30293936, 31345425, 32829317, 33740630, 33994402). This variant has been identified in 2/249776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different variants affecting the same codon are considered to be disease-causing (ClinVar variation ID: 183093, 251362, 251365, 251361), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Uncertain significance, 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	subject mutated among 2600 FH index cases screened = 1 , family member = 1 /FH-France / Software predictions: Damaging -
Pathogenic, criteria provided, single submitter	clinical testing	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	Jan 16, 2023	The patient was admitted to the Interventional Cardiology department, Nhan Dan Gia Dinh hospital, Vietnam and was diagnosed with stable angina CCS III (confirmed by Coronary MSCT), Triple vessel disease, and Hypertension. Furthermore, she had hyperlipidemia with a sign of Arcus Senilis in both eyes. Before that, her older sister was also diagnosed with hyperlipidemia. Her genetic testing showed a heterogeneous variant of LDLR gene, c.664T>C (p.Cys222Arg). This variant affects the p.Cys222 amino acid residue in LDLR. Despite its “Conflicting interpretations of pathogenicity” in ClinVar (only 4 over 10 submissions recorded with pathogenic status), her clinical features strongly suggest the diagnosis of Familial Hypercholesterolemia. This mutation record is expected to contribute to the clinical significance of the variant. The Interventional Cardiology department, Nhan Dan Gia Dinh hospital, Ho Chi Minh City, Vietnam played a main role in diagnosing this case. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.664T>C (p.Cys222Arg) variant is classified as a Likely pathogenic variant for Familial Hypercholesterolemia by applying evidence codes PM2, PM1, PM3, PS4_supporting, 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: PM2: PopMax MAF = 0.0001098 (0.01%) in East Asian exomes (gnomAD v2.1.1) PM1: Variant meets PM2 and alters Cys222, one of the cysteine residues listed. PM3: Variant meets PM2 and is identified in two index cases with homozygous FH phenotype (LDL mmol/L = 17.9 and 14.09 respectively), PMID: 15823276 PS4_supporting: Variant meets PM2 and is identified in at least 5 index cases who fulfill SB possible/definite FH or DLCN>=6 criteria for FH from GeneDx Inc., Ambry Genetics, and the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) PP3 : REVEL = 0.966. PP4: Variant meets PM2 and identified in at least 2 FH case from GeneDx Inc, 1 FH case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), and 1 FH case from Ambry Genetics, all of them fulfilling SB criteria for possible/definite FH or DLCN > 6. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 13, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 05, 2008	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 16, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A5 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); This variant is associated with the following publications: (PMID: 25043216, 22883975, 15823276, 15823288, 12553167) -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 222 of the LDLR protein (p.Cys222Arg). This variant is present in population databases (rs577934998, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15823276, 22883975, 25043216; Invitae). This variant is also known as C201R and c.541T>C. ClinVar contains an entry for this variant (Variation ID: 226332). 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). This variant disrupts the p.Cys222 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 7573037, 24671153), which suggests that this may be a clinically significant amino acid residue. 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	Aug 22, 2022	Variant summary: LDLR c.664T>C (p.Cys222Arg) 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 8e-06 in 249776 control chromosomes (gnomAD). c.664T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (examples: Hooper_2012, Martn-Campos_2018, and Leren_2021). These data indicate that the variant is very likely to be associated with disease. Other variants located at the same codon have been reported in association with Hypercholesterolaemia (C222G, C222F, C222W, C222Y; HGMD). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

The p.C222R variant (also known as c.664T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 664. The cysteine at codon 222 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration, also referred to as p.C201R, has been reported in multiple patients with familial hypercholesterolemia (Damgaard D et al. Atherosclerosis. 2005;180:155-60; Sözen MM et al. Atherosclerosis. 2005;180:63-71; Hooper AJ et al. Atherosclerosis. 2012;224:430-4; Zhao X et al. Int J Cardiol. 2014;176:e15-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, internal structural analysis predicts this alteration to disrupt a cysteine-cysteine bridge in a conserved motif in a region of known function (Fass D et al. Nature. 1997;388(6643):691-3). Alterations at the same amino acid position, p.C222G (Taylor A et al. Clin Genet. 2010;77:572-80), C222F (Fouchier SW et al. Hum Genet. 2001;109:602-15), p.C222W (Medeiros AM et al. Genet Med. 2016;18:316-24) and p.C222Y (Koivisto UM et al. Am J Hum Genet. 1995;57:789-97), have also been reported in individuals with hypercholesterolemia. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.6

H;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-11

D;D;D;D

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.96

MutPred

0.95

Loss of methylation at K223 (P = 0.0253);Loss of methylation at K223 (P = 0.0253);.;Loss of methylation at K223 (P = 0.0253);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

1.0

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

Other links and lift over