19-11113413-T-C

Position:

• chr19-11113413-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3 PP4 PS3 PS4_Moderate PP1_Strong

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PP1_Strong, PM2, PS4_Moderate, PP3 and PP4) 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: PS3 - Level 1 assay - PMID:25741862 - CHO cells, WB+FACS+CLSM, 7% low-density lipoprotein particle receptor biosynthetic process; 5% low-density lipoprotein particle binding; 10% low-density lipoprotein particle clearance.PP1_strong - 6 informative meioses in 3 families identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1).PS4_moderate - Variant meets PM2. Variant identified in 9 index cases.PP3 - REVEL: 0,907. PP4 - Variant meets PM2. Variant identified in 9 index cases fulfilling specific clinical criteria for FH (6 cases with Simon-Broome from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 3 cases with Simon-Broome criteria published in PMID:20538126). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585400/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 29)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.92

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 14 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.1322T>C	p.Ile441Thr	missense_variant	9/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1322T>C	p.Ile441Thr	missense_variant	9/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 21, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/100 healthy control individuals -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 09, 2021	NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PP1_Strong, PM2, PS4_Moderate, PP3 and PP4) 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: PS3 - Level 1 assay - PMID:25741862 - CHO cells, WB+FACS+CLSM, 7% low-density lipoprotein particle receptor biosynthetic process; 5% low-density lipoprotein particle binding; 10% low-density lipoprotein particle clearance. PP1_strong - 6 informative meioses in 3 families identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 9 index cases. PP3 - REVEL: 0,907. PP4 - Variant meets PM2. Variant identified in 9 index cases fulfilling specific clinical criteria for FH (6 cases with Simon-Broome from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 3 cases with Simon-Broome criteria published in PMID: 20538126). -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 18, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 441 of the LDLR protein (p.Ile441Thr). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25741862). 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. ClinVar contains an entry for this variant (Variation ID: 251783). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 11810272, 17087781, 20538126, 25741862, 27206935; Invitae). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 09, 2018	Pathogenic variant based on current evidence: This missense variant (also known as p.Ile420Thr in the mature protein) is located in the LDLR type B repeat 2 of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies in CHO cells have shown that this variant causes a near complete loss of LDLR activity (~10% of normal) with retention in the endoplasmic reticulum as the precursor form (PMID: 25741862). This variant has been shown to segregate with hypercholesterolemia in 9 of 10 affected individuals from four different Portuguese families (PMID: 25741862). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Different missense variants at the same codon (p.Ile441Asn and p.Ile 441Met) are considered to be disease-causing. Based on available evidence, this variant is classified as Pathogenic. -

LDLR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 08, 2023

The LDLR c.1322T>C variant is predicted to result in the amino acid substitution p.Ile441Thr. This variant also described using legacy nomenclature as p.Ile420Thr, has been documented in several reports as a causative variant for Hypercholesterolemia (Fouchier et al. 2001. PubMed ID: 11810272; Medeiros et al. 2010. PubMed ID: 20828696; Benito-Vicente et al. 2015. PubMed ID: 25741862; Huang et al. 2021. PubMed ID: 33994402). Functional studies showed that this variant significantly reduced LDLR activity (Benito-Vicente et al. 2015. PubMed ID: 25741862). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The p.I441T pathogenic mutation (also known as c.1322T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1322. The isoleucine at codon 441 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in multiple individuals with familial hypercholesterolemia from a range of ethnic backgrounds (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Chiu CY et al. Metab. Clin. Exp., 2005 Aug;54:1082-6; Benito-Vicente A et al. Genet. Med., 2015 Dec;17:980-8; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8). Functional studies demonstrated significantly reduced LDLR activity with precursor protein retained in the endoplasmic reticulum (Benito-Vicente A et al. Genet. Med., 2015 Dec;17:980-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.2	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		0.93	P;.;.;.;.;.
Vest4		0.76
MutPred		0.96		Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);.;.;.;Loss of stability (P = 0.0012);
MVP		1.0
MPC		0.82
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
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: rs879254862; hg19: chr19-11224089;