rs193922566

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM1PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) 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: PM1 - Variant meets PM2 and alters Cys340, one of the cysteine residues listed.PM2 - PopMax MAF = 0.00005782 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1).PP3 - REVEL: 0,98. PP4 - Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria and in 1 FH case published in PMID:30592178 who fulfills DLCN criteria.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases with clinical FH criteria. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023408/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

16

2

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 9.55

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 Likely_pathogenic. Variant got 7 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

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 linkuse as main transcript	c.1055G>A	p.Cys352Tyr	missense_variant	7/18	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.1055G>A	p.Cys352Tyr	missense_variant	7/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.00000798

AC:

2

AN:

250660

Hom.:

0

AF XY:

0.00000737

AC XY:

1

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

5

AN:

1460982

Hom.:

0

Cov.:

31

AF XY:

0.00000275

AC XY:

2

AN XY:

726822

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

32

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	Disrupt disulfide bridge between Cys340 and Cys352. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 08, 2021	NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) 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: PM1 - Variant meets PM2 and alters Cys340, one of the cysteine residues listed. PM2 - PopMax MAF = 0.00005782 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL: 0,98. PP4 - Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria and in 1 FH case published in PMID: 30592178 who fulfills DLCN criteria. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases with clinical FH criteria. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000036450, PMID:1301956). Different missense change at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000251617,VCV000251618,VCV000251619,VCV000251622, PMID:21376320,17347910, 20809525, 9974426). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98>=0.6, 3CNET: 0.99>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Nov 27, 2020	The c.1055G>A(p.Cys352Tyr) missense variant (also previously known asp.Cys331Tyr and FH-Mexico-2 allele) is localized in exon 7 of 18 of LDLR in the EGF-like domain. This variant has been identified in multiple individuals diagnosed with hypercholesterolemia in heterozygous, homozygous and compound heterozygous states [PMIDs:1301956, 19717150, 21722902, 22698793, 23064986, 25234566]. Experimental studies have shown that this variant results in a significantly reduced LDLR activity in cells from patients [PMIDs: 1301956, 19026292]. This variant is absent in gnomADv3 and present in gnomADv2 at a very low frequency (2/250660alleles, allele frequency = 0.000007979; no homozygoytes) indicating it is not a common benign variant in the populations represented in this database. In silico predictors suggest this variant is Damaging (Provean; score: -10.55;SIFT; score:0). This variant has been reported in Clinvar as a Pathogenic /Likely Pathogenic variant [Variation ID:36450]. Missense variants at the same residue (Cys352Ser, Cys352Arg, Cys352Phe, Cys352Trp) have also been reported in affected individuals with familial hypercholesterolemia. Given the current evidence regarding its pathogenicity, the c.1055G>A(p.Cys352Tyr) variant identified in the LDLR gene is reported as Likely Pathogenic. -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2020	Variant summary: LDLR c.1055G>A (p.Cys352Tyr) results in a non-conservative amino acid change located in the EGF-like domain and EGF-like calcium-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several variants at the same codon have been associated with Familial Hypercholesterolemia (C352R, C352F, C352S, C352W), as well as the immediately adjacent codons, suggesting the locus is important for gene function.The variant allele was found at a frequency of 8e-06 in 250860 control chromosomes. c.1055G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Kolansky_2008, Ahmad_2012, Vaca_2011, Magana Torres_2014, Tichy_2012, Alonso_2009, Junyent_2010, Mabuchi_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal LDL receptor activity (Kolansky_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 352 of the LDLR protein (p.Cys352Tyr). This variant is present in population databases (rs193922566, gnomAD 0.006%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 19717150, 21722902, 22698793, 23064986, 25234566). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys331Tyr. ClinVar contains an entry for this variant (Variation ID: 36450). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This missense variant (also known as p.Cys331Tyr in the mature protein and as FH Mexico-2) replaces cysteine with tyrosine at codon 352 in the EGF-like repeat A of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study has shown that this variant results in a significantly reduced LDLR activity in cells from a patient compound heterozygous for this variant and p.Cys364Arg (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 21722902, 22698793, 23064986, 32331935, 33533259, 34037665, 35929461; Color internal data). This variant has also been observed in both the compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 1301956, 25234566). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 25234566). This variant has been identified in 2/250660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon: p.Cys352Phe, p.Cys352Trp, and p.Cys352Ser, are considered to be disease-causing (ClinVar variation ID: 251619, 251622, 251617), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 06, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH Mexico-2 and p.(C331Y) due to alternate nomenclature; This variant is associated with the following publications: (PMID: 1301956, 19026292, 19318025, 22698793, 32331935, 30592178, 32719484, 34037665, 25014035, 28391882, 19717150, 29576406, 23064986, 21722902, 37808210, 38003014, 31491741, 25234566, 2988123, 12459547) -

LDLR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2023

The LDLR c.1055G>A variant is predicted to result in the amino acid substitution p.Cys352Tyr. This variant was reported in patients with hypercholesterolemia (For example, reported as FH Mexico-2 or C331Y in Hobbs et al. 1992. PubMed ID: 1301956; Sturm. 2021. PubMed ID: 34037665). Incomplete penetrance was noted in a family (Magaña Torres et al. 2014. PubMed ID: 25234566). Of note, other missense variants affecting the same amino acid (p.Cys352Ser, p.Cys352Arg, p.Cys352Phe) have also been reported as causative for hypercholesterolemia (HGMD database; Hobbs et al. 1992. PubMed ID: 1301956). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11221442-G-A). This variant is interpreted as likely pathogenic or pathogenic in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/RCV000030122.12/). This variant is interpreted as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The p.C352Y pathogenic mutation (also known as c.1055G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1055. The cysteine at codon 352 is replaced by tyrosine, 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 mutation (also reported as p.C331Y and Mexico-2) has been observed in multiple FH cohorts (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Alonso R et al. em>Clin. Biochem. 009;42:899-903; Vaca G et al. Atherosclerosis. 2011;218:391-6; Ahmad Z et al. Circ Cardiovasc Genet. 2012;5:666-75; Tichý L et al. Atherosclerosis. 2012;223:401-8). This alteration has also been detected in the homozygous state in a proband with homozygous FH, and segregated with disease on both sides of the family, although with incomplete penetrance (Magaña Torres MT et al. J Clin Lipidol. 2014;8:525-7). In addition, this mutation segregated with disease in one small family tested by our laboratory. Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like domain (Ambry internal data). Furthermore, several alterations in the same codon (p.C352S, p.C352W, p.C352R, and p.C352F) have also been associated with FH (Bertolini S et al. Arterioscler Thromb Vasc Biol. 1999;19(2)408-18; Widhalm K et al. J Inherit Metab Dis. 2007;30(2):239-47; Marduel M et al. Hum. Mutat. 2010;31(11):E1811-24; Chiou KR et al. Atherosclerosis. 2011;216:383-9). 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

0.99

BayesDel_addAF

Pathogenic

0.46

D

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;.;.;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.98

D

MetaRNN

Pathogenic

1.0

D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.8

H;.;.;.;.;H

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.64

T

PROVEAN

Pathogenic

-10

D;D;D;D;D;D

REVEL

Pathogenic

0.98

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

0.98

MutPred

0.98

Gain of phosphorylation at C352 (P = 0.0517);Gain of phosphorylation at C352 (P = 0.0517);.;.;.;Gain of phosphorylation at C352 (P = 0.0517);

MVP

1.0

MPC

1.1

ClinPred

1.0

D

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.99

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922566; hg19: chr19-11221442;