rs121908032

Variant names:

• chr19-11129562-G-A
• rs121908032
• NM_000527.5:c.2439G>A

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.2439G>A​(p.Trp813*) variant causes a stop gained change. 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: 31)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.16
• Publications: 7 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 19-11129562-G-A is Pathogenic according to our data. Variant chr19-11129562-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3703.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.2439G>A	p.Trp813*	stop_gained	Exon 17 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2439G>A	p.Trp813*	stop_gained	Exon 17 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Feb 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.2439G>A p.Trp813Ter variant (rs121908032), also known as p.Trp792Ter in legacy nomenclature, is reported in the literature in multiple individuals affected with familial hypercholesterolaemia (selected references: Lehrman 1985, Loux 1991, Taylor 2007). This variant is reported in ClinVar (Variation ID: 3703) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon in exon 17 (of 18) and truncates a critical cytoplasmic domain. This variant has been shown to greatly reduced LDL receptor activity (Lehrman 1985), and other nearby truncating variants, or deletions of exons 17-18 are considered disease causing (Jelassi 2009 and Alonso 2009). Based on available information, this variant is considered to be pathogenic. References: Alonso R et al. Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. Clin Biochem. 2009 Jun;42(9):899-903. PMID: 19318025. Jelassi A et al. Limited mutational heterogeneity in the LDLR gene in familial hypercholesterolemia in Tunisia. Atherosclerosis. 2009 Apr;203(2):449-53. PMID: 18757057. Lehrman MA et al. Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain. Cell. 1985 Jul;41(3):735-43. PMID: 3924410. Loux N et al. Recurrent mutation at aa 792 in the LDL receptor gene in a French patient. Hum Genet. 1991 Jul;87(3):373-5. PMID: 1677927. Taylor A et al. Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. Clin Genet. 2007 Jun;71(6):561-8. PMID: 17539906. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.26	T
MetaRNN	Pathogenic	0.79	D
PhyloP100		5.2
PROVEAN	Benign	1.0	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Vest4		0.53
MVP		0.99
GERP RS		4.8
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)		0.0		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: rs121908032; hg19: chr19-11240238; COSMIC: COSV99370253; COSMIC: COSV99370253;