rs140807148

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000527.5(LDLR):c.325T>C(p.Cys109Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,076 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C109F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 4.99

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 11 ACMG points.

PM1

In a disulfide_bond (size 12) in uniprot entity LDLR_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) 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 chr19-11105232-G-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 19-11105231-T-C is Pathogenic according to our data. Variant chr19-11105231-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251156.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=5}. Variant chr19-11105231-T-C is described in Lovd as [Pathogenic]. Variant chr19-11105231-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.325T>C	p.Cys109Arg	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.325T>C	p.Cys109Arg	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250272

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135616

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461076

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726864

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

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6Uncertain:1

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Cys109Arg variant in LDLR has been reported in at least 7 individuals (including 2 Czech, 2 Portuguese, 1 Dutch, 1 German, and 1 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 16250003, 1301956, 16314194, 22698793, 24627126), and has been identified in 0.001771% (2/112906) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140807148). 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 pathogenic and likely pathogenic in ClinVar (Variation ID: 251156). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional missense variant (p.Cys109Ser) is likely pathogenic with a different amino acid change at the same position and has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (PMID: 12009418; Variation ID: 3743). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_Supporting, PS4_Moderate, PP3, PP1 (Richards 2015). -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

0/190 non-FH alleles; 0/77 healthy control individuals -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 11, 2018

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The mutation occurs at protein level at position 109 (position 88 of the mature protein) to exchange the amino acid cysteine for arginine. This change has already been described in the literature as FH Munster-1 allele, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. It leads to a strong reduction of LDL receptor activity. PMID: 11313767, 1301956 -

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disrupt disulfide bridge between Cys109 and Cys121. -

Familial hypercholesterolemia

Pathogenic:2

Apr 24, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.324_325delinsTC (p.Cys109Arg) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in individuals with hypercholesterolemia (PMID: 11313767, 34037665, 35741760, 20145306). The c.324_325delinsTC (p.Cys109Arg) variant is located in a mutational hotspot for pathogenic variations associated with hypercholesterolemia (PMID: 24404629, 34906454). Different amino acid changes at the same residue (p.Cys109Gly; p.Cys109Phe; p.Cys109Ser; p.Cys109Trp; p.Cys109Tyr) have been previously reported in individuals with hypercholesterolemia (PMID: 33269076, 31893465, 32044282, 12009418, 23375686, 30293936, 9544745, 34037665). The c.324_325delinsTC (p.Cys109Arg) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Based on the available evidence, c.324_325delinsTC (p.Cys109Arg) is classified as Pathogenic. -

Feb 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 251156). This variant is also known as p.C88R. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 9544745, 11313767, 12009418, 14974088, 19843101, 20145306, 22698793, 32104752). This variant is present in population databases (rs140807148, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 109 of the LDLR protein (p.Cys109Arg). -

not provided

Pathogenic:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PS1, PM2, PM5, PP4, PS4:Supporting -

Cardiovascular phenotype

Pathogenic:1

Sep 12, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C109R pathogenic mutation (also known as c.325T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 325. The cysteine at codon 109 is replaced by arginine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This alteration, also known as FH Munster-1 or p.C88R, has been reported in individuals with familial hypercholesterolimia (FH) from a number of ethnic groups (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Robles-Osorio L et al. Arch Med Res. 2006;37:102-8; Tichý L et al. Atherosclerosis. 2012;223:401-8). A different nucleotide change resulting in the same amino acid alteration (c.324_325delGTinsTC) has also been detected in patients with FH (Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Chmara M et al. J Appl Genet. 2010;51:95-106). In addition, alterations at the same amino acid position, p.C109S and p.C109Y (also known as p.C88S and p.C88Y, respectively), have also been reported in association with FH (Pisciotta L et al. Biochim Biophys Acta. 2002;1587:7-11; Bertolini S et al. Atherosclerosis. 2013;227:342-8; Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Chmara M et al. J Appl Genet. 2010;51:95-106). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.5

H;.;.;H

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.9

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.99

D;.;.;.

Vest4

0.57

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.99

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