rs879254905

Positions:

chr19-11113623-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3PP4PS4_SupportingPM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.914.It is above 0.75, so PP3 is Met.PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases (1 index case with Simon-Broome/DLCN criteria of definite FH (LDL=12,4 mmol/L and tendinous xanthomas) from Ireland (PMID 8535447); 3 index case with Simon-Broome criteria of possible FH from UK (PMID 17539906); 1 index case with FH criteria (LDL-C >95th percentile and AD inheritance pattern of hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease) from The Netherlands (PMID 21382890), so PS4_Supporting is met.PP4 - Variant meets PM2 and is identified in at least one index case who fulills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585457/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:8U:1

Conservation

PhyloP100: 6.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1447T>C	p.Trp483Arg	missense_variant	10/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1447T>C	p.Trp483Arg	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460986

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726862

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:8Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jun 04, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 29, 2023	The NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.914. It is above 0.75, so PP3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases (1 index case with Simon-Broome/DLCN criteria of definite FH (LDL=12,4 mmol/L and tendinous xanthomas) from Ireland (PMID 8535447); 3 index case with Simon-Broome criteria of possible FH from UK (PMID 17539906); 1 index case with FH criteria (LDL-C >95th percentile and AD inheritance pattern of hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease) from The Netherlands (PMID 21382890), so PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in at least one index case who fulills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 15, 2024	The LDLR c.1447T>C (p.Trp483Arg) variant (also known as W462R) has been reported in the published literature in individuals with coronary artery disease (CAD) (PMID: 31727422 (2020)), and familial hypercholesterolemia (FH) (PMIDs: 34037665 (2021), 31345425 (2019), 23833242 (2013), 21382890 (2011), 17539906 (2007), 16250003 (2005), 16159606 (2005), 15823280 (2005), 11845603 (2001), 10559517 (1999), 9039985 (1997), 8535447 (1995)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2024	Identified in multiple individuals with familial hypercholesterolemia referred for genetic testing at GeneDx and in published literature (PMID: 16250003, 8535447, 17539906, 18700895, 27680772, 34037665); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18700895, 16250003, 19837725, 17539906, 27680772, 9039985, 34037665, 8535447, 22881376, 31727422) -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2018

The p.Trp483Arg variant in LDLR has been reported in at least 7 individuals with familial hypercholesterolemia and segregated with disease in 6 affected members of 1 family (Ward 1995, Fouchier 2005, Taylor 2007, Martin 2016). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp483Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PM2; PS4_Moderate; PP1_Moderate; PP3. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2024

The p.W483R variant (also known as c.1447T>C), located in coding exon 10 of the LDLR gene, results from a T to C substitution at nucleotide position 1447. The tryptophan at codon 483 is replaced by arginine, an amino acid with dissimilar properties. This variant (also known as W462R) was originally reported in a heterozygous proband and six affected family members in a family with a definite diagnosis of familial hypercholesterolemia (FH) (Ward AJ et al. Hum. Mutat., 1995;6:254-6). This variant was later reported in a patient who was compound heterozygous for this alteration and another likely pathogenic missense alteration in LDLR (Taylor A et al. Clin. Genet., 2007 Jun;71:561-8). This variant has also been detected in additional FH cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Martin R et al. Atherosclerosis, 2016 11;254:8-13). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 483 of the LDLR protein (p.Trp483Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 8535447, 17539906, 19837725, 21382890, 27680772). This variant is also known as p.W462R. ClinVar contains an entry for this variant (Variation ID: 251847). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant disrupts the p.Trp483 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26892515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

1.0

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;.;.;.;H

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-13

D;D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.80

MutPred

0.96

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);.;.;.;Gain of solvent accessibility (P = 0.0584);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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