rs199570811

Variant names:

• chr19-11102734-G-A
• rs199570811
• NM_000527.5:c.261G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS3_Supporting PM2 PVS1 PP4 PS4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.261G>A (p.Trp87Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met.PS4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID:21990180.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID:21990180.PS3_supporting - Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584814/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.89

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 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.261G>A	p.Trp87*	stop_gained	Exon 3 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.261G>A	p.Trp87*	stop_gained	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

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

- -

Jun 07, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.261G>A (p.Trp87Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PS3_supporting - Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PVS1, PM2, PP4:Moderate, PS4:Moderate, PS3:Supporting -

Familial hypercholesterolemia Pathogenic:1

Aug 08, 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.Trp87*) 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 LDLR-related conditions (PMID: 19318025, 34456049). ClinVar contains an entry for this variant (Variation ID: 251100). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.90
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs199570811; hg19: chr19-11213410;