19-11116882-T-G

Position:

• chr19-11116882-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4_Supporting PP3 PP4 PP1_Moderate PM2 PS3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1729T>G (p.Trp577Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PP1_moderate, PM2, PP3, PS4_supporting, PP4, 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: PS3: Level 1 assays: PMID 25378237: Heterologous cells, FACS assays -10-15% LDL-LDLR binding; 5% LDL-LDLR uptake; 5% cell surface LDLR---- activity is below 70% of wild-type, so functional study is consistent with damaging effect.PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.937.PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute; 1 case with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation))PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585585/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 7.88

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 11 ACMG points.

• 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.
• PP1: 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	c.1729T>G	p.Trp577Gly	missense_variant	12/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1729T>G	p.Trp577Gly	missense_variant	12/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6

Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.1729T>G (p.Trp577Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PP1_moderate, PM2, PP3, PS4_supporting, PP4, 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: PS3: Level 1 assays: PMID 25378237: Heterologous cells, FACS assays -10-15% LDL-LDLR binding; 5% LDL-LDLR uptake; 5% cell surface LDLR ---- activity is below 70% of wild-type, so functional study is consistent with damaging effect. PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.937. PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute; 1 case with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded. -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely 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 , family member = 1 with co-segregation / Other mutation at same codon/software prediction damaging -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Jan 22, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GENinCode PLC	May 17, 2024	The c.1729T>G p.(Trp577Gly) missense variant in LDLR has been reported in 3 FH patients meeting clinical criteria, including a patient with a clinical diagnosis of FH after alternative causes of high cholesterol were excluded (PS4_SUPPORTING, PP4_ SUPPORTING; ClinGen FH VCEP and internal data). The variant has been reported to segregate with FH in 4 affected meioses (PP1_MODERATE; ClinGen FH VCEP data). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE). This variant meets level 1 pathogenic functional study criteria with <70% of wild-type activity in expression/biosynthesis, LDL binding and LDL internalization (PS3_STRONG; PMID: 25378237) and has a REVEL score of 0.937 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 577 of the LDLR protein (p.Trp577Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 17347910, 19318025, 27830735, 33740630). ClinVar contains an entry for this variant (Variation ID: 252000). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25378237). This variant disrupts the p.Trp577 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11013454, 12436241, 15823276, 17347910, 18339137). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-13	D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.94
MutPred		0.95		Loss of catalytic residue at W577 (P = 0.0029);Loss of catalytic residue at W577 (P = 0.0029);.;.;.;Loss of catalytic residue at W577 (P = 0.0029);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.99

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: rs879255000; hg19: chr19-11227558;