19-11110767-C-G

Position:

chr19-11110767-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.1056C>G(p.Cys352Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,914 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. C352F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -1.20

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:

LDLR (HGNC:):

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 2) in uniprot entity LDLR_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11110766-G-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 19-11110767-C-G is Pathogenic according to our data. Variant chr19-11110767-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11110767-C-G 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.1056C>G	p.Cys352Trp	missense_variant	7/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1056C>G	p.Cys352Trp	missense_variant	7/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460914

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6

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, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 09, 2024	This missense variant replaces cysteine with tryptophan at codon 352 in the EGF-like repeat A of the LDLR protein. This variant is also known as p.Cys331Trp in the mature protein, and as FH Avellino-1 in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies in cultured fibroblasts from both heterozygous and homozygous individuals have shown that this variant causes a significant reduction in LDLR activity as well as LDL binding and internalization (PMID: 9974426, 11585102). This variant has been reported in more than 10 individuals affected with familial hypercholesterolemia (PMID: 10735632, 10978268, 11585102, 11810272, 11851376, 23375686, 27824480, 30710474, 31345425, 32977124, 34456200). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 9974426, 26723464, 36422519). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon: p.Cys352Tyr, p.Cys352Phe, and p.Cys352Ser, are considered to be disease-causing (ClinVar variation ID: 36450, 251619, 251617), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 23, 2019	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2019

The p.C352W pathogenic mutation (also known as c.1056C>G), located in coding exon 7 of the LDLR gene, results from a C to G substitution at nucleotide position 1056. The cysteine at codon 352 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in an EGF-like domain. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (also referred to as C331W and FH Avellino-1) has been reported in the homozygous state in a pediatric patient reported to have a clinical diagnosis of homozygous familial hypercholesterolemia (FH) and significantly reduced LDL-receptor activity; however, experimental data were not shown (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999;19:408-18). This variant has been detected in additional individuals from FH cohorts (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Van Gaal LF et al. Mol. Cell. Probes, 2001;15:329-36; Bertolini S et al. Atherosclerosis, 2013;227:342-8; Gabová D et al. Physiol Res, 2017;66:75-84). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). In addition, other variants affecting this codon (e.g., p.C352Y and p.C352S) have also been reported in association with FH (Magaña Torres MT et al. J Clin Lipidol. 2014;8:525-7; Medeiros AM et al. Genet. Med. 2016;18:316-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 26, 2017

Variant summary: The LDLR c.1056C>G (p.Cys352Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120928 control chromosomes. This variant was reported in multiple patients with familial hypercholesterolemia (FH), including a homozygous patient whose phenotype was more severe than the heterozygous patients (Bertolini_Atherosclerosis_2013, Fouchier_HG_2001), including . A functional study suggested that the variant causes a defective LDL receptor, though the data was not provided for independent assessment (Bertolini_Atherosclerosis_2013). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

8.9

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.;.;.;.;.

Eigen

Benign

-0.084

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

H;.;.;.;.;H

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-10

D;D;D;D;D;D

REVEL

Pathogenic

0.88

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

0.96

MutPred

0.97

Loss of disorder (P = 0.0493);Loss of disorder (P = 0.0493);.;.;.;Loss of disorder (P = 0.0493);

MVP

1.0

MPC

0.94

ClinPred

1.0

GERP RS

-4.6

Varity_R

0.99

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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