rs879254981

Positions:

• chr19-11116188-C-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.1681C>T​(p.Gln561*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,194 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.27

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 19-11116188-C-T is Pathogenic according to our data. Variant chr19-11116188-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 251965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116188-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1681C>T	p.Gln561*	stop_gained	11/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1681C>T	p.Gln561*	stop_gained	11/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460194 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726552

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6

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	subjects mutated among 2600 FH index cases screened = 9 , family member = 1 with co-segregation -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2019

The p.Gln561X variant in LDLR (also described as p.Gln440X in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), including one homozygous individual where the variant segregated with disease in at least 4 affected family members (Feher 1993, Webb 1996, Amsellem 2002, Vandrovcova 2013, ClinVar submission accessions: SCV000503382.1, SCV000583860.1). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 561, which is predicted to lead to a truncated or absent protein. Additionally, in vitro functional studies support an impact on protein function (Webb 1996). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2, PP1_Supporting, PS3_Supporting, PS4_Moderate. -

LDLR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2023

The LDLR c.1681C>T variant is predicted to result in premature protein termination (p.Gln561*). This variant is also described using legacy nomenclature as p.Gln540*, has been reported in the heterozygous and homozygous states in individuals with hypercholesterolemia (Webb et al. 1996. PubMed ID: 9026534; Amsellem et al. 2002. PubMed ID: 12436241). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251965). This variant is also known as Gln540*. This premature translational stop signal has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 8292093, 32041611). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln561*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	38
DANN	Uncertain	0.98
Eigen	Benign	0.080
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.94
GERP RS		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254981; hg19: chr19-11226864;