rs875989921

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000527.5(LDLR):c.1448G>A(p.Trp483*) 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 1,460,932 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.88

Variant links:

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 links:

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6886 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 19-11113624-G-A is Pathogenic according to our data. Variant chr19-11113624-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 226356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113624-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1448G>A	p.Trp483*	stop_gained	Exon 10 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1448G>A	p.Trp483*	stop_gained	Exon 10 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460932

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:7

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PVS1 -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 17, 2013

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 10, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 23, 2024

First Hospital of Lanzhou University, Lanzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

A 38-year-old female proband carried compound heterozygous variations(c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery disease. The patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband's father, both brothers and daughter carried the c.1448G> A variant. All of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family. -

not provided

Pathogenic:2

Apr 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1448G>A (p.Trp483*) variant (also known as Trp462Stop or W462stop) causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature in multiple individuals affected with familial hypercholesterolemia (FH) in a heterozygous (PMID: 7903864 (1994), 23375686 (2013), 34456049 (2022)), homozygous (PMID: 7903864 (1994), 27206941 (2016), 30526649 (2018)), or compound heterozygous state (PMID: 27206941 (2016)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 27206941 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Mar 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant results in an altered whole LDLR life-cycle (PMID: 19073363); 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; Also known as p.(W462*); This variant is associated with the following publications: (PMID: Zhou2017[article], 32793292, 27206935, 25907359, 27170061, 30876527, 30949068, 18247305, 27578104, 30415195, 10657581, 28235710, 29233637, 32759540, 28502495, 30108616, 23375686, 25846081, 30526649, 33994402, 31161821, 32629184, 30400955, 26608663, 25525159, 34037665, 34456049, 35979295, 36991406, Zhan2023[preprint], 38236436, 27206941, 38018368, 38297435, 19073363, 7903864, 33746137, 38003014) -

Familial hypercholesterolemia

Pathogenic:2

Jul 10, 2024

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.Trp483*) 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 familial hypercholesterolemia (PMID: 7903864, 18247305). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226356). For these reasons, this variant has been classified as Pathogenic. -

Jan 04, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 10 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 25 individuals affected with familial hypercholesterolemia (PMID: 23375686, 25846081, 27170061, 28235710, 28502495, 29233637). 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. Based on available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Jun 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W483* pathogenic mutation (also known as c.1448G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1448. This changes the amino acid from a tryptophan to a stop codon within coding exon 10. This mutation, often reported in the Chinese population (also referred to as W462* or Trp462Stop), has been detected in the heterozygous, homozygous and compound heterozygous states in many individual with heterozygous or homozygous familial hypercholesterolemia (FH), and has shown segregation with FH in families (Sun XM et al. Arterioscler Thromb, 1994 Jan;14:85-94; Schmidt H et al. Atherosclerosis, 2000 Feb;148:431-2; Cheng XH et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2008 Feb;25:55-8; Jiang L et al. J Clin Lipidol, 2016 Dec;10:538-546.e5; Marco-Benedí V et al. Atherosclerosis, 2022 May;349:211-218). Functional studies have shown this variant to adversely impact protein function (Cheng XH et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2008 Feb;25:55-8; Wang L et al. Nutr Metab Cardiovasc Dis, 2009 Jul;19:391-400; Jiang L et al. J Clin Lipidol, 2016 Dec;10:538-546.e5). 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

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

Vest4

0.95

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over