19-11129606-A-G

Variant names:

• chr19-11129606-A-G
• rs28942085
• NM_000527.5:c.2483A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_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 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.11
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr19-11129605-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 252345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 3704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2483A>G	p.Tyr828Cys	missense	Exon 17 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2483A>G	p.Tyr828Cys	missense	Exon 17 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.2360A>G	p.Tyr787Cys	missense	Exon 16 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2483A>G	p.Tyr828Cys	missense	Exon 17 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2741A>G	p.Tyr914Cys	missense	Exon 17 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2483A>G	p.Tyr828Cys	missense	Exon 17 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

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

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

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.

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).

not provided Pathogenic:1 Other:1

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

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)

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.21	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.85	D
PhyloP100		9.1
PROVEAN	Benign	-0.15	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.088	T
Vest4		0.65
MVP		0.98
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28942085; hg19: chr19-11240282;