19-11129606-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000527.5(LDLR):c.2483A>G(p.Tyr828Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y828H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

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:9O:1

Conservation

PhyloP100: 9.11

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 mutagenesis_site Abolishes interaction with ARRB2. (size 0) in uniprot entity LDLR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr19-11129605-T-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 19-11129606-A-G is Pathogenic according to our data. Variant chr19-11129606-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11129606-A-G is described in Lovd as [Pathogenic]. Variant chr19-11129606-A-G 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.2483A>G	p.Tyr828Cys	missense_variant	Exon 17 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.2483A>G	p.Tyr828Cys	missense_variant	Exon 17 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727218

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5

Apr 11, 1986

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 29, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial hypercholesterolemia

Pathogenic:2

Dec 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 3955657, 16740646). ClinVar contains an entry for this variant (Variation ID: 3704). This variant is also known as p.Tyr807Cys, or JD Bari. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 23375686, 25461735, 28126585, 31387896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 828 of the LDLR protein (p.Tyr828Cys). -

Mar 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with cysteine at codon 828 in the cytoplasmic domain of the LDLR protein. This variant is also known as p.Tyr807Cys in the mature protein, and as FH Bari in the literature. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. Functional studies have shown that this variant causes defective receptor internalization with absence of LDLR activity (PMID: 189940, 1968060, 3104336, 3955657, 10224150). This variant has been reported in more than ten individuals affected with familial hypercholesterolemia (PMID: 189940, 1301956, 8882879, 23375686, 25461735, 33508743, 33740630, 35626767). This variant has also been observed in homozygous state in several individuals affected with severe homozygous familial hypercholesterolemia (PMID: 31387896). It has been shown that this variant segregates with disease in multiple affected individuals from one large family (PMID: 31387896). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:1Other:1

May 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Published functional studies demonstrate a damaging effect through defective uptake, internalization, and degradation (Davis et al., 1986; Ranheim et al., 2006; Thormaehlen et al., 2015); Also denoted as Y807C and FH J.D-Bari due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 23375686, 28126585, 23733886, 189940, 8882879, 19446849, 200368, 31387896, 20145306, 25461735, 3955657, 23105264, 32041611, 33740630, 32719484, 33508743, Thajer2022, 25647241, 16740646) -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Cardiovascular phenotype

Pathogenic:1

Jan 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y828C pathogenic mutation (also known as c.2483A>G), located in coding exon 17 of the LDLR gene, results from an A to G substitution at nucleotide position 2483. The tyrosine at codon 828 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been described in several patients with familial hypercholesterolemia (FH) (Brown MS et al. Cell, 1976 Dec;9:663-74; Goldstein JL et al. Cell, 1977 Nov;12:629-41; Reshef A et al. Hum Genet. 1996;98:581-6; Chmara M et al. J Appl Genet. 2010;51:95-106; Bertolini S et al. Atherosclerosis. 2013;227:342-8). In functional in vitro analyses, this variant has demonstrated decreased ability to bind and internalize low-density lipoprotein (LDL), thus inhibiting endocytosis (Davis CG et al. Cell. 1986;45:15-24). Internal structural analysis suggests that this variant, which impacts the NPXY motif required for receptor internalization, will disrupt protein function (Chen WJ et al. J Biol Chem. 1990;265(6):3116-23; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.21

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.85

PROVEAN

Benign

-0.15

Sift

Pathogenic

0.0

Sift4G

Benign

0.088

Vest4

0.65

MVP

0.98

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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