rs879254719

Positions:

• chr19-11107493-G-A
• chr19-11107493-G-C
• chr19-11107493-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4_Moderate PP1_Moderate PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.919G>A (p.Asp307Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PP1_Moderate, PM2, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines(https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PP1_Moderate: Variant segregates with FH phenotype in at least 5 informative meiosis from 2 different families (PMID:32706999, Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)). PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PS4_Moderate:Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill SBpossible or definite criteria for FH from different labs (PMID:32706999, Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3: REVEL = 0.865PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definiteFH after alternative causes of high cholesterol were excluded (PMID:32706999). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585195/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.87

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.919G>A	p.Asp307Asn	missense_variant	6/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.919G>A	p.Asp307Asn	missense_variant	6/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:1

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	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000527.5:c.919G>A (chr19:11107493) in LDLR was detected in 12 heterozygotes out of 58K WGS Icelanders (MAF= 0,010%). Following imputation in a set of 166K Icelanders (18 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 2.53, P= 1.29e-18), Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 2.35, P= 6.00e-17) and myocardial infarction using 25692 cases and 320832 controls (OR= 4.72, P= 3.43e-02). This variant has been reported in ClinVar previously as likely pathogenic and as a variant of uncertain significance. Based on ACMG criteria (PS4, PP1, PP5) this variant classifies as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 28, 2016	This sequence change replaces aspartic acid with asparagine at codon 307 of the LDLR protein (p.Asp307Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 22698793). This variant is also known as p.Asp286Asn in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;.;.;.;.;H
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.84
MutPred		0.90		Gain of catalytic residue at D307 (P = 0.0367);Gain of catalytic residue at D307 (P = 0.0367);.;.;.;Gain of catalytic residue at D307 (P = 0.0367);
MVP		1.0
MPC		0.80
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99

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

Other links and lift over

dbSNP: rs879254719; hg19: chr19-11218169; COSMIC: COSV104577536; COSMIC: COSV104577536;