rs875989900

Positions:

Variant summary

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

The NM_000527.5(LDLR):c.400T>C(p.Cys134Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,516 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. C134F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

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 disulfide_bond (size 15) in uniprot entity LDLR_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) 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 chr19-11105307-G-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 19-11105306-T-C is Pathogenic according to our data. Variant chr19-11105306-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105306-T-C 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.400T>C	p.Cys134Arg	missense_variant	4/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.400T>C	p.Cys134Arg	missense_variant	4/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251176

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461516

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727094

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Mar 24, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 09, 2023	This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LDLR: PM1, PM2, PM5, PP4:Moderate, PS4:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2025	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; Also known as p.(C113R); This variant is associated with the following publications: (PMID: 7548065, 18325082, 23375686, 7603991, 29233637, 15256764, 12417285, 31447099, 32759540, 32770674, 12730724, 30415195, 11462246, 34037665, 28179607, 7979249, 28349240, 26582918, 25921077, 10735632, 12459547, 2988123) -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 134 of the LDLR protein (p.Cys134Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10735632, 11462246, 12730724, 25921077). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys113Arg. ClinVar contains an entry for this variant (Variation ID: 226322). 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. 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.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 23375686), 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	Color Diagnostics, LLC DBA Color Health	Oct 24, 2022	This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Different missense variants occurring at the same codon (p.Cys134Tyr, p.Cys134Phe, p.Cys134Trp) are known to be disease-causing (ClinVar variation ID: 251203, 251204, 251205). This p.Cys134Arg variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2017

The p.Cys134Arg (previously p.Cys113Arg) variant in LDLR has been reported in >4 individuals with familial hypercholesterolemia (FH) and segregated with disease with 2 affected relatives from 1 family (Lombardi 2000, Nauck 2001, El Messal 2 003, Han 2015, ClinVar: Variation ID 226322). It has also been identified in 1/1 11580 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs875989900). Computational prediction tools and conservation analysis suggest that the p.Cys134Arg variant may impact the prote in. Additionally, other missense variants at this position (p.Cys134Tyr, p.Cys13 4Phe, p.Cys134Gly and p.Cys134Trp) have been reported in individuals with famili al hypercholesterolemia (Human Gene Mutation Database: Stenson et al., 2017), In summary, although additional studies are required to fully establish its clinic al significance, the p.Cys134Arg variant is likely pathogenic for autosomal domi nant FH. ACMG/AMP criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2023

The p.C134R pathogenic mutation (also known as c.400T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 400. The cysteine at codon 134 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been described in patients with familial hypercholesterolemia (FH) from various ethnic groups (Lombardi MP et al. Clin Genet. 2000;57:116-24; Nauck MS et al. Hum Mutat. 2001;18:165-6; El Messal M et al. J Hum Genet. 2003;48:199-203; Han Y et al. Int J Pediatr Otorhinolaryngol. 2015;79:1148-51). Other alterations involving the same amino acid, p.C134F (c.401G>T), p.C134W (c.402C>G), and p.C134Y (c.401G>A), have also been reported in FH cohorts (Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. 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

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

1.0

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.6

H;.;.;H

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-11

D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.98

MutPred

0.95

Loss of catalytic residue at L135 (P = 0.0869);Loss of catalytic residue at L135 (P = 0.0869);.;Loss of catalytic residue at L135 (P = 0.0869);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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