rs138947766

Variant names:

• chr19-11116883-G-A
• rs138947766
• NM_000527.5:c.1730G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11116883-G-A
• chr19-11116883-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.1730G>A​(p.Trp577*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.83
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 19-11116883-G-A is Pathogenic according to our data. Variant chr19-11116883-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1730G>A	p.Trp577*	stop_gained	Exon 12 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1730G>A	p.Trp577*	stop_gained	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000236 Hom.: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 5 , family members = 4 with co-segregation / Other nonsens mutation at same codon with < 2% LDLR Activity -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Trp577Ter (sometimes called p.Trp556Ter) variant in LDLR has been reported in at least 5 individuals (including 1 Russian, 1 French, and 1 from the UK) with Familial Hypercholesterolemia in ClinVar and the literature (Variation ID: 375821; PMID: 1301956, 23680767, 26802169), and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 375821). This nonsense variant leads to a premature termination codon at position 577, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. Multiple variants in the same position as p.Trp577Ter have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 252001, 252000, 252003, 406163, 252004, 226370). One pathogenic variant with the same amino acid change as this variant, c.1731G>A, has been reported in association with disease in ClinVar, supporting that this variant may be pathogenic (Variation ID: 226370). The phenotype of an individual homozygous for this variant is highly specific for Familial Hypercholesterolemia with <2% LDL receptor activity (PMID: 1301956). Individuals who are homozygous for pathogenic variants are known to have a more severe phenotype than heterozygous individuals. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and another pathogenic variant with a different nucleotide change but the same amino acid change. ACMG/AMP Criteria applied: PVS1, PS1, PM2, PM1_Supporting, PS4_Supporting, PP4 (Richards 2015). -

Familial hypercholesterolemia Pathogenic:2

Jul 17, 2024

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1730G>A p.(Trp577Ter) variant in LDLR is a nonsense variant predicted to create a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been seen in FH patients meeting clinical criteria (PS4_SUPPORTING; PMIDs 23680767, 26802169, 35929461, internal data). This variant is absent from gnomAD v2.1.1, so PM2_MODERATE is met. Functional studies in homozygous patient fibroblasts showed this variant decreased LDL receptor activity to <2% of wild type (PS3_MODERATE; PMID 1301956). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Jan 16, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp577*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 23680767, 24507775, 26802169). ClinVar contains an entry for this variant (Variation ID: 375821). A different variant (c.1731G>A) giving rise to the same protein effect observed here (p.Trp577*) has been determined to be pathogenic (PMID: 1301956, Invitae). This suggests that this variant is also likely to be causative of disease. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Oct 19, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W577* pathogenic mutation (also known as c.1730G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1730. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This variant has been detected in several individuals with familial hypercholesterolemia (Vandrovcova J et al. Genet Med, 2013 Dec;15:948-57; Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45; Wintjens R et al. J Lipid Res, 2016 Mar;57:482-91; Rieck L et al. Clin Genet, 2020 11;98:457-467). 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	0.59
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.8
Vest4		0.94
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs138947766; hg19: chr19-11227559;