rs875989933

Positions:

• chr19-11120106-G-A
• chr19-11120106-G-C
• chr19-11120106-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.1860G>A​(p.Trp620*) variant causes a stop gained change involving the alteration of a 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.78

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11120106-G-A is Pathogenic according to our data. Variant chr19-11120106-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 252089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120106-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1860G>A	p.Trp620*	stop_gained	13/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1860G>A	p.Trp620*	stop_gained	13/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 17, 2017	The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband’s family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband's family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic. -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2022	This sequence change creates a premature translational stop signal (p.Trp620*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 252089). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 25846081). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 01, 2023	This variant changes 1 nucleotide in exon 13 in the LDLR type B repeat 6 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least two individuals affected with familial hypercholesterolemia (PMID: 20809525, 25846081, 28235710) and in one individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 26, 2022

PP1, PM2_supporting, PVS1 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2022

The p.W620* pathogenic mutation (also known as c.1860G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1860. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This variant has been reported in individuals with familial hypercholesterolemia (FH), segregating with disease in two families (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Fan LL et al. Appl Biochem Biotechnol, 2015 May;176:101-9; Xiang R et al. Atherosclerosis, 2017 03;258:84-88; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	52
DANN	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.97
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs875989933; hg19: chr19-11230782;