rs267607213

chr19-11100286-G-Achr19-11100286-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.131G>A(p.Trp44Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,622 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25
• Conservation: PhyloP100: 9.48

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 19-11100286-G-A is Pathogenic according to our data. Variant chr19-11100286-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11100286-G-A is described in Lovd as [Pathogenic]. Variant chr19-11100286-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.131G>A	p.Trp44Ter	stop_gained	2/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.131G>A	p.Trp44Ter	stop_gained	2/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461622 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727096

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:16

Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 19, 2017	This c.131G>A (p.Trp44*) variant in the LDLR gene is predicted to is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with familial hypercholesterolemia (PMID: 1301956, 8850176). The c.131G>A (p.Trp44*) variant in the LDLR gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change creates a premature termination codon at position 44 in exon 2 (of 18) of LDLR, p.(Trp44*), also known as p.Trp23* and FH Cincinnati-5. It is expected to result in nonsense mediated decay, and loss of function is a well-established mechanism of disease for this gene (ClinGen). The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). The variant is a recurrent mutation that has been identified in individuals with either homozygous or heterozygous familial hypercholesterolaemia, and segregates with disease in multiple families. Additionally, loss of LDL receptor activity has been identified in patient fibroblasts from an individual with this variant (PMID: 8850176, 1301956). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2_Supporting, PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 05, 1986	- -
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 = 10 , family members = 2 with co-segregation / FH-Cincinnati-5, 2 to 5% LDLR activity -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	ACMG Guidelines: Pathogenic (ii) -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jul 22, 2008	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 2023	This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 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 over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31048103). 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. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 16, 2016	The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of four genes associated with familial hypercholesterolemia: LDLR, APOB, PCSK9 and LDLRAP1. Results showed that the following variant was identified (see report below): p.Trp44* (c.131G>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given sufficient case data and the loss of function nature of this variant we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least nine unrelated cases of FH (not including this patient's family). This amounts to strong case data. Some of these individuals are reported as p.W23X in the literature due to alternate transcript terminology. See PMIDs: 1301956, 22390909, 21382890, 11668627, 22698793, 20145306, 16542394, 20506408). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as this variant results in a null allele (Hobbs et al., 1992); Reported in ClinVar (ClinVar Variant ID# 3741; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32665702, 32331935, 32719484, 32041611, 31447099, 31048103, 22390909, 26036859, 12417285, 9157944, 8645371, 8850176, 1301956, 25525159) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 05, 2021	PVS1, PS4, PM2, PS3_moderate, PM3_supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial hypercholesterolemia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2021	Variant summary: LDLR c.131G>A (p.Trp44X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251254 control chromosomes. In a cross sectional ascertainment, c.131G>A has been widely reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Huijgen_2012, Luirink_2019, Dron_2020). These data indicate that the variant is likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 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 over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31048103). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 09, 2023	This sequence change creates a premature translational stop signal (p.Trp44*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). ClinVar contains an entry for this variant (Variation ID: 3741). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 23, 2015

The p.Trp44X variant in LDLR has been reported in a large number (>500) of indiv iduals with hypercholesterolemia (Hobbs 1992, Huijgen 2010, Chmara 2010, Duskova 2011, Fouchier 2015). It was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 44, which is predic ted to lead to a truncated or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in familial hypercholesterolemia. In summar y, this variant meets our criteria to be classified as pathogenic for hyperchole sterolemia in an autosomal dominant manner (http://www.partners.org/personalized medicince/LMM) based upon the predicted impact to the protein, its presence in a large number of affected individuals, and absence from controls. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The p.W44* pathogenic mutation (also known as c.131G>A), located in coding exon 2 of the LDLR gene, results from a G to A substitution at nucleotide position 131. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This mutation has been reported in multiple unrelated individuals with familial hypercholesterolemia (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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	0.54
Cadd	Pathogenic	46
Dann	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;D
Vest4		0.84
GERP RS		5.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607213; hg19: chr19-11210962;