chr19-11105258-G-T

Position:

chr19-11105258-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000558518.6(LDLR):c.352G>T(p.Asp118Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D118A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11U:1O:1

Conservation

PhyloP100: 4.37

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in ENST00000558518.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant 19-11105258-G-T is Pathogenic according to our data. Variant chr19-11105258-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105258-G-T is described in Lovd as [Pathogenic]. Variant chr19-11105258-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.352G>T	p.Asp118Tyr	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.352G>T	p.Asp118Tyr	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250932

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135810

show subpopulations

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461302

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726974

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000496

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5Uncertain:1

Uncertain significance, flagged submission	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	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 13, 2023	The c.352G>T (p.Asp118Tyr) variant of the LDLR gene, that encodes for low density lipoprotein receptor, has been identified in heterozygous status in several unrelated individuals (>10) who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID:10978268, 11317362, 17196209, 20045108, 23375686, 28965616, 28958694). This variant has also been reported in homozygous or compound heterozygous status in multiple affected individuals (at least 6) with severe FH (PMID:10978268, 11317362, 23375686, 9974426, 28965616). In-vitro functional studies on cultured patient derived fibroblasts have shown that this variant results in 30% of normal LDLR activity when compound heterozygote with another well-known pathogenic variant, p.Val523Met (ClinVar ID: 3696) (PMID: 9974426, 23375686). This variant lies in the mutational hot spot (amino acids 105-232) of a well-established functional domain critical for LDLR protein function. This variant is found to be rare (3/250932; 0.00001196) in the general population database (gnomAD) and interpreted as likely pathogenic by several submitters in the ClinVar database (ClinVar ID: 183085). Therefore, the c.352G>T (p.Asp118Tyr) variant in LDLR gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	May 10, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Sep 03, 2015	- -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 118 of the LDLR protein (p.Asp118Tyr). This variant is present in population databases (rs730882080, gnomAD 0.003%). This missense change has been observed in individuals with LDLR-related conditions (PMID: 9974426, 11317362, 23375686, 25487149, 28161202, 28965616, 31345425). This variant is also known as D97Y, FH-Napoli-3 or Naples-3. ClinVar contains an entry for this variant (Variation ID: 183085). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces aspartic acid with tyrosine at codon 118 of the LDLR protein. This variant is also known as p.Asp97Tyr in the mature protein, and FH Naples 3 in the literature. This variant alters a conserved AA1 residue in the LDLR type A repeat 3 of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study has shown that this variant results in 30% of normal LDLR activity when in compound heterozygous state with a different pathogenic LDLR missense variant (PMID: 9974426). This variant has shown an unclear functional consequence in a high throughput screening assay in HeLa cells (PMID: 25647241). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9974426, 28161202, 28965616, 28958694, 31947532, 35795214; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in at least two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 23375686, 31947532, 36325061). This variant has been identified in 3/250932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2024	Variant summary: LDLR c.352G>T (p.Asp118Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250932 control chromosomes. c.352G>T has been reported in the literature in multiple heterozygous individuals affected with Familial Hypercholesterolemia, as well as multiple compound heterozygous individuals affected with Homozygous Familial Hypercholesterolemia (e.g., Bertolini_1999, Scicali_2018, Di Taranto_2020, Du_2022). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect. One study demonstrates that LDLR activity in an individual with the variant is approximately 30%, however this individual also carried the pathogenic variant p.V523M (Betolini_1999). Another study investigating whether this variant is disruptive demonstrated unclear results (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 31947532, 36325061, 28958694, 25647241). ClinVar contains an entry for this variant (Variation ID: 183085). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 19, 2022	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 15, 2020

The p.Asp118Tyr variant in LDLR has been identified in the heterozygous state in at least 6 individuals with hypercholesterolemia and segregated with disease in > 4 affected relatives with definite or probable familial hypercholesterolemia (FH) from at least 2 families (Bertolini 1999 PMID: 9974426, Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Romano 2010 PMID: 20045108, Bertolini 2013 PMID: 23375686, Scicali 2017 PMID: 28958694, Pirillo 2017 PMID: 28965616, Trinder 2019 PMID: 31345425). It has also been reported in 1 homozygote and 3 compound heterozygotes (with additional pathogenic LDLR variants) with hypercholesterolemia, at least 3 of whom had a more severe presentation (Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Bertolini 2013 PMID: 23375686). Additionally, this variant has been reported in 2 individuals with early myocardial infarction (Thormaehlen 2015 PMID: 25647241). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183085) and has also been identified in 0.003% (3/111436) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that the variant has only a mild impact protein function (Bertolini 2013 PMID: 23375686, Thormaehlen 2015 PMID: 25647241). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4_Moderate, PM3, PP1, PM2_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2023

The p.D118Y variant (also known as c.352G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 352. The aspartic acid at codon 118 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, also known as p.D97Y, has been reported primarily in Italian familial hypercholesterolemia (FH) cohorts (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Liguori R et al. Hum. Mutat., 2001 May;17:433; Campagna F et al. Atherosclerosis, 2008 Jan;196:356-64; Romano M et al. Atherosclerosis, 2010 Jun;210:493-6; Minicocci I et al. J. Pediatr., 2017 Apr;183:100-107.e3; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 Jan;28:35-43). Reduced LDL-R activity (30% of the control) was reported in a compound heterozygous FH patient who also carried the p.V523M pathogenic mutation (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18). Based on internal structural analysis, this variant is predicted to disrupt a linear motif (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;.;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.6

M;.;.;M

MutationTaster

Benign

0.76

D;D;D;D;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.99

D;.;.;.

Vest4

0.59

MutPred

0.57

Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);.;Loss of loop (P = 0.1258);

MVP

1.0

MPC

0.89

ClinPred

0.95

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.48

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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