rs746939188

Positions:

• chr19-11116105-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PVS1 PS4_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1598G>A (p.Trp533Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PP4 and 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: PVS1 - variant is nonsense upstream of amino acid 830, so PVS1 is met.PM2 - PopMax MAF = 0.000008792 (0.0009%) in European Non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP4 - variant meets PM2.identified in: - 1 index case who fulfills SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge.- 1 index case who fulfills SB criteria from Marduel et al. 2010 (PMID:20809525).so PP4 is met.PS4_supporting - variant meets PM2 and was identified in 2 unrelated index cases from different labs (please see PP4 for details), so PS4_Supporitng is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA035378/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR ENST00000558518.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 9.87

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 12 ACMG points.

• PVS1: 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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1598G>A	p.Trp533Ter	stop_gained	11/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1598G>A	p.Trp533Ter	stop_gained	11/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 28, 2022	The NM_000527.5(LDLR):c.1598G>A (p.Trp533Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PP4 and 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: PVS1 - variant is nonsense upstream of amino acid 830, so PVS1 is met. PM2 - PopMax MAF = 0.000008792 (0.0009%) in European Non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP4 - variant meets PM2. identified in: - 1 index case who fulfills SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. - 1 index case who fulfills SB criteria from Marduel et al. 2010 (PMID: 20809525). so PP4 is met. PS4_supporting - variant meets PM2 and was identified in 2 unrelated index cases from different labs (please see PP4 for details), so PS4_Supporitng is met. -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 07, 2021

This sequence change creates a premature translational stop signal (p.Trp533*) 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia or myocardial infarction (PMID: 20809525, 25487149). ClinVar contains an entry for this variant (Variation ID: 251926). This variant is present in population databases (rs746939188, ExAC 0.002%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.93
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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

Other links and lift over

dbSNP: rs746939188; hg19: chr19-11226781;