rs879254566

Variant names:

• chr19-11105440-T-G
• rs879254566
• NM_000527.5:c.534T>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.534T>G​(p.Asp178Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D178G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: -0.373
• Publications: 5 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 19 ACMG points.

• PM1: In a hotspot region, there are 31 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr19-11105439-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251286.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, 0.992
• PP5: Variant 19-11105440-T-G is Pathogenic according to our data. Variant chr19-11105440-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.534T>G	p.Asp178Glu	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.534T>G	p.Asp178Glu	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6

Jun 04, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp178Glu variant in LDLR (also reported at p.Asp157Glu in the literature) has been reported in at least 6 individuals with familial hypercholesterolemia (FH; Weiss 2000, Widhalm 2007, CCHMC pers comm., ClinVar Variation ID: 251287) and segregated with disease in 2 affected relatives from 1 family (CCHMC pers comm.). This variant was absent from large population studies. Computational prediction tools and conservation analyses are consistent with pathogenicity. Other variants at this position (p.Asp178Asn, p.Asn178Gly, p.Asn178His, p.Asn178Tyr, p.Asn178Val) have been reported in individuals with FH in the Human Gene Mutation Database (Stenson 2017) and in ClinVar, suggesting that changes at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PM5_Supporting. -

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

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Nov 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS5,PM1,PM2,PP2,PP5,BP1 -

Familial hypercholesterolemia Pathogenic:2

Aug 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 178 of the LDLR protein (p.Asp178Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11196104; Invitae). This variant is also known as p.Asp157Glu. ClinVar contains an entry for this variant (Variation ID: 251287). 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 with a positive predictive value of 95%. This variant disrupts the p.Asp178 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12436241, 16389549), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jan 03, 2022

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.Asp157Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 178 of the LDLR protein. This variant is located in the ligand binding domain in a region critical for LDL binding (PMID: 2600087, 3417658). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 11196104, 17347910, 33418990; Shakhtshneider et al, 2019, DOI: 10.1016/j.atherosclerosis.2019.06.883). 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 Likely Pathogenic. -

Dyslipidemia Pathogenic:1

Jul 17, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Nov 07, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D178E pathogenic mutation (also known as c.534T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 534. The aspartic acid at codon 178 is replaced by glutamic acid, an amino acid with highly similar properties. This variant (also referred to as p.D157E) has been reported in multiple individuals with features consistent with familial hypercholesterolemia (FH) (Weiss N et al. J. Inherit. Metab. Dis., 2000 Dec;23:778-90; Widhalm K et al. J. Inherit. Metab. Dis., 2007 Apr;30:239-47; Madar L et al. Genes (Basel). 2022 01;13(1); Timoshchenko O et al. Int J Mol Sci, 2023 Dec;25; external communication; Ambry internal data). Internal structural analysis indicates that this variant, which impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A4, is expected to have a deleterious impact on protein function (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62; 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant 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	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;H
PhyloP100		-0.37
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.94	P;.;.;.
Vest4		0.79
MutPred		0.90		Gain of catalytic residue at W180 (P = 0.1034);Gain of catalytic residue at W180 (P = 0.1034);.;Gain of catalytic residue at W180 (P = 0.1034);
MVP		1.0
MPC		0.78
ClinPred		1.0	D
GERP RS		-4.0
PromoterAI		-0.0062	Neutral
Varity_R		0.96
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs879254566; hg19: chr19-11216116;