rs879255217

Positions:

• chr19-11129599-C-A
• chr19-11129599-C-G
• chr19-11129599-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):​c.2476C>A​(p.Pro826Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,798 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: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.73

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 19-11129599-C-A is Pathogenic according to our data. Variant chr19-11129599-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11129599-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2476C>A	p.Pro826Thr	missense_variant	17/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2476C>A	p.Pro826Thr	missense_variant	17/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1/Software predictions: Conflicting -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 06, 2023

The LDLR c.2476C>A; p.Pro826Thr variant (rs879255217) is reported in the literature in individuals affected with familial hypercholesterolemia, in either the heterozygous or compound heterozygous state (Bertolini 2020, Di Taranto 2020, Futema 2013). This variant is also reported in ClinVar (Variation ID: 252343), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism.. The proline at codon 826 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.883). Based on available information, this variant is considered to be likely pathogenic. References: Bertolini S et al. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Di Taranto MD et al. A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia. J Clin Med. 2020 Jan 14;9(1):219. PMID: 31947532. Futema M et al. Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis. 2013 Jul;229(1):161-8. PMID: 23669246. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2023

The p.P826T variant (also known as c.2476C>A), located in coding exon 17 of the LDLR gene, results from a C to A substitution at nucleotide position 2476. The proline at codon 826 is replaced by threonine, an amino acid with highly similar properties. This variant has been reported in an individual from a familial hypercholesterolemia (FH) cohort (Futema M et al. Atherosclerosis, 2013 Jul;229:161-8), and co-occurred with a pathogenic mutation in the LDLR gene in siblings reported to have homozygous FH presentation; however, details were limited (Di Taranto MD et al. J Clin Med. 2020 Jan;9(1)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 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. -

Familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 24, 2019

This missense variant (also known as p.Pro805Thr in the mature protein) replaces proline with threonine at codon 826 of the LDLR 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). This variant changes a highly conserved proline residue from the Asn-Pro-Val-Tyr motif in the cytoplasmic domain that interacts with the clathrin adaptor protein LDLRAP1 and is required for coated pit-mediated internalization of LDLR (PMID: 1968060, 22509010). Although functional studies have not been performed for this variant, a different amino acid substitution at this position (Pro to Ala) has been shown to significantly reduce LDL internalization to 25% of wild type activity, while having no impact on LDL binding to LDLR at the cell surface (PMID: 1968060). This study demonstrates a critical role of proline residue at codon 826 in LDLR function. This variant has been reported in individuals affected with familial hypercholesterolemia (dissertation by D’Agostino 2014, PMID: 23669246). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.59
MutPred		0.61		Gain of methylation at K830 (P = 0.1249);.;.;.;Gain of methylation at K830 (P = 0.1249);
MVP		1.0
MPC		0.86
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs879255217; hg19: chr19-11240275;