19-11106652-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.782G>T(p.Cys261Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.99

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 19-11106652-G-T is Pathogenic according to our data. Variant chr19-11106652-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11106652-G-T 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.782G>T	p.Cys261Phe	missense_variant	Exon 5 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.782G>T	p.Cys261Phe	missense_variant	Exon 5 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251480

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

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:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6

Apr 12, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.782G>T (p.Cys261Phe) variant has previously been detected in several patients with familial hypercholesterolemia [legacy: 240 in PMID 9767373, 16542394]. The variant was also detected in a 13 y/o female, compound heterozygous for this variant and a loss of function variant [PMID 10422803]. Two siblings carried the same c.782G>T (p.Cys261Phe) heterozygous variant with only one clinically presenting hypercholesterolemia. In vitro assays showed that although the cells produced a detectable protein, cells expressing the mutant protein were unable to mediate uptake and degradation of LDL [PMID 10422803]. This variant has been reported in only one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/19-11217328-G-T). This variant is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Cys261Phe change to be deleterious. This variant is thus classified as likely pathogenic. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 24, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous c.782G>T variant identified in LDLR has previously been reported in the literature [PMIDs: 9767373, 10422803, 16542394,24507775, 31447099, 33740630] and in ClinVar [ClinVar ID: 3740] in individuals with familial hypercholesterolemia. The variant has been observed in four alleles with no homozygotes in the population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common variant in the populations represented in those databases. The predicted p.(Cys261Phe) variant (previously reported as p.(Cys240Phe)) resides in the exon 5 of this 18-exon gene and is located within one of the cysteine-rich LDL-receptor class A repeat domains, which contains six disulphide-bound cysteines that are critical for protein structure and stability [PMID:7603991]. In LDL receptors, the class A domains form the binding site for LDL and calcium. In vitro functional studies demonstrated delayed processing of the LDLreceptor [PMID: 10422803]. In silico prediction algorithms are in favor of damaging effect of the variant on the encoded transcript (CADD v1.6= 29.9; REVEL= 0.974). Based on available evidence this heterozygous c.782G>T p.(Cys261Phe) missense variant identified in LDLR is reported as Pathogenic. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.782G>T (p.Cys261Phe) variant (also known as p.Cys240Phe) in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in multiple individuals (>10) affected with Familial Hypercholesterolemia (FH) (PMID:9767373, 15199436, 16542394, 19062533, 33955087, 36648309). This variant has also been observed in compound heterozygous status (with a loss-of-function variant, p.Tyr167*) in a proband with severe FH (LDL-C: 16.6mmol). Proband's sister and mother, who were carrier for this variant manifested heterozygous FH phenotype, however another sibling who is a carrier had normal phenotype suggesting incomplete penetrance (PMID: 10422803). Functional studies using patient derived fibroblasts showed very low cholesterol esterification (<2%) and markedly reduced LDL uptake and degradation (8% and <2%, respectively). Transfection of the mutant, p.Cys261Phe, protein in CHOldlA7 cells showed detectable protein but impaired LDL uptake and degradation (PMID: 10422803). This variant affects one of the sixty highly conserved cysteine residues located within an LDLR class A 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-silico computational prediction tools suggest that the p.Cys261Phe variant may have deleterious effect on the protein function (REVEL score: 0.974). This variant is found to be rare (3/251480; 0.00001193) in the general population database, gnomAD and interpreted as likely pathogenic/ pathogenic by several submitters in the ClinVar database (ClinVar ID: 3740). Therefore, the c.782G>T (p.Cys261Phe) variant in LDLR gene is classified as pathogenic. -

Familial hypercholesterolemia

Pathogenic:2

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 261 of the LDLR protein (p.Cys261Phe). This variant is present in population databases (rs121908040, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9767373, 10422803, 16542394, 19062533). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as C240F. ClinVar contains an entry for this variant (Variation ID: 3740). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 10422803). 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. -

Mar 22, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Cys240Phe in the mature protein) is located in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897). Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. An experimental study has demonstrated that the variant protein shows delayed processing and accumulates as a precursor protein in the cells, resulting in defective LDL uptake and degradation (PMID: 10422803). Computational splicing tools suggest that this variant may not impact the RNA splicing. This variant has been reported in individuals with hypercholesterolemia in Sweden and Russia in compound heterozygosity with another deleterious variant in the LDLR gene (PMID: 10422803, 19062533). This variant has been identified in 10/121250 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Feb 13, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys261Phe variant in LDLR (also described as p.Cys240Phe in the literature ), has been reported in at least 5 individuals with familial hypercholesterolemi a (FH) in the heterozygous state (Brusgaard 2006, Ekstrom 1999, Ekstrom 1998, Le ren 2004), and in 1 individual with homozygous FH who were compound heterozygote for this variant and a second pathogenic variant in LDLR, where it segregated w ith disease in 2 relatives in one family (Ekstrom 1999). This variant has also b een reported in Clinvar (Variation ID# 3740). In vitro functional studies provid e some evidence that the p.Cys261Phe variant may impact receptor uptake and degr adation (Ekstrom 1999). This variant has been identified in 2/111718 European ch romosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs121908040). This frequency is low enough to be consistent with t he frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Cys261Phe variant may impact the prote in. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys261Phe variant is likely pathogenic. ACMG/AMP Cr iteria applied (Richards 2015): PM2, PM3, PS4_Moderate, PP3, PS3_Supporting. -

Hypercholesterolemia

Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

Oct 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.782G>T (p.Cys261Phe) variant (also known as C240F) has been reported in the published literature in multiple individuals with familial hypercholesterolemia (FH) (PMIDs: 33740630 (2021), 19062533 (2008), 16542394 (2006), 15199436 (2004), 9767373 (1998)), and shown to have deleterious effects on LDL uptake and degradation in vitro (PMID: 10422803 (1999)). In one family, this variant occurred with a second LDLR pathogenic variant in an individual with homozygous FH presentation, but segregated with disease in only one of two of the proband's siblings (PMID: 10422803 (1999)). The frequency of this variant in the general population, 0.000012 (3/251480 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, this variant is classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Sep 21, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C261F variant (also known as c.782G>T), located in coding exon 5 of the LDLR gene, results from a G to T substitution at nucleotide position 782. The cysteine at codon 261, located in LDLR class A repeat 6, is replaced by phenylalanine, 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 particular cysteine alteration, also referred to as C240F, has been reported in individuals with hypercholesterolemia and in FH cohorts (Ekström U et al. Eur J Clin Invest. 1998;28:740-7; Leren TP et al. Semin Vasc Med. 2004;4:75-85; Brusgaard K et al. Clin Genet., 2006;69:277-83; Voevoda MI et al. Genetika. 2008;44(10):1374-8). This alteration was detected in compound heterozygosity with a second LDLR alteration in a proband with severe, early onset disease, and was seen alone in two affected relatives and one unaffected relative. In vitro studies indicated this variant resulted in impaired LDL uptake and degradation (Ekström U et al. Clin Genet. 1999;55:332-9). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 6 (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.6

H;.;.;.;H

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-10

D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.94

MVP

1.0

MPC

1.0

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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