rs879254803

chr19-11111588-T-Cchr19-11111588-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):c.1135T>C(p.Cys379Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,182 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C379Y) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.83

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 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain 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 chr19-11111589-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11111588-T-C is Pathogenic according to our data. Variant chr19-11111588-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11111588-T-C is described in Lovd as [Pathogenic]. Variant chr19-11111588-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1135T>C	p.Cys379Arg	missense_variant	8/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1135T>C	p.Cys379Arg	missense_variant	8/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 14, 2020	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 14, 2022	PS4, PS3, PM2, PP3 -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant (also known as p.Cys358Arg in the mature protein) replaces cysteine with arginine at codon 379 in the EGF-like repeat B of the LDLR protein. 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). Functional studies using patient-derived fibroblasts have shown that this variant causes a significant reduction in LDLR activity in the homozygous state (PMID: 1301956, 9974426). Another functional study using heterozygous patient-derived lymphocytes has shown that this variant causes a significant reduction in residual LDLR activity compared to wild-type (PMID: 21865347). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11317362, 15241806, 17196209, 25682026, 26342331, 30710474, 32759540, 33955087, 34037665). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 9974426, 1301956, 9974426, 11317362, 15823276, 23375686, 26723464, 27578108, 32977124), indicating that this variant contributes to disease. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 09, 2023	PS3, PP3, PM5, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2023	The LDLR c.1135T>C; p.Cys379Arg variant (rs879254803), also known as Cys358Arg in legacy nomenclature, is reported in the literature in the heterozygous, homozygous and compound heterozygous sates in numerous individuals affected with familial hypercholesterolemia (Bertolini 2020, Campagna 2008, Hobbs 1992, Sozen 2005, Wang 2020). Fibroblasts/ lymphocytes isolated from homozygous and heterozygous individuals have significantly reduced LDLR activity (Liguori 2001, Romano 2011). This variant is also reported in ClinVar (Variation ID: 251685) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 379 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.985). Based on available information, this variant is considered to be pathogenic. References: Bertolini S et al. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Campagna F et al. Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening. Atherosclerosis. 2008 Jan;196(1):356-364. PMID: 17196209. Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Liguori R et al. LDL receptor cDNA sequence analysis in familial hypercholesterolemia patients: 5 novel mutations with high prevalence in families originating from southern Italy. Hum Mutat. 2001 May;17(5):433. PMID: 11317362. Romano M et al. An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations. J Lipid Res. 2011 Nov;52(11):2095-100. PMID: 21865347. Sozen MM et al. The molecular basis of familial hypercholesterolaemia in Turkish patients. Atherosclerosis. 2005 May;180(1):63-71. PMID: 15823276. Wang H et al. Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. J Atheroscler Thromb. 2020 Dec 1;27(12):1288-1298. PMID: 32759540. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2023	Identified in a patient with early-onset myocardial infarction in published literature (Khera et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a significant reduction in LDL receptor activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C358R); This variant is associated with the following publications: (PMID: 1301956, 34037665, 32759540, 33955087, 30710474, 34040191, 32220565, 26723464, 35379577, 30586733, 32977124, 23375686, 21865347) -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2023	This missense variant (also known as p.Cys358Arg in the mature protein) replaces cysteine with arginine at codon 379 in the EGF-like repeat B of the LDLR protein. 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). Functional studies using patient-derived fibroblasts have shown that this variant causes a significant reduction in LDLR activity in the homozygous state (PMID: 1301956, 9974426). Another functional study using heterozygous patient-derived lymphocytes has shown that this variant causes a significant reduction in residual LDLR activity compared to wild-type (PMID: 21865347). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11317362, 15241806, 17196209, 25682026, 26342331, 30710474, 32759540, 33955087, 34037665). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 9974426, 1301956, 9974426, 11317362, 15823276, 23375686, 26723464, 27578108, 32977124), indicating that this variant contributes to disease. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 379 of the LDLR protein (p.Cys379Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9852677, 11317362, 15241806, 23375686, 25682026). It has also been observed to segregate with disease in related individuals. This variant is also known as FH Naples-1 and C358R. ClinVar contains an entry for this variant (Variation ID: 251685). 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 have shown that this missense change affects LDLR function (PMID: 1301956, 21865347). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The p.C379R pathogenic mutation (also known as c.1135T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1135. The cysteine at codon 379 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the EGF-like B domain. This alteration (with legacy nomenclature p.C358R and FH Naples-1) has been reported in the heterozygous, compound heterozygous, and homozygous states in multiple unrelated individuals with familial hypercholesterolemia (FH) (e.g., Liguori R et al. Hum. Mutat. 2001;17:433; Sözen MM et al. Atherosclerosis. 2005;180:63-71; Campagna F et al. Atherosclerosis. 2008;196:356-64). Fibroblasts derived from several unrelated patients homozygous for this alteration exhibit 15-30% of normal LDLR activity, and lymphocytes obtained from a heterozygous patient also show reduced LDLR activity (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol. 1999;19:408-18; Romano M et al. J. Lipid Res. 2011;52:2095-100). Internal structural analysis indicates that this alteration disrupts a disulfide bond known to be crucial for the structural stability of the region (Ambry internal data). 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). In addition, a variant at the same codon, p.C379Y, has also been associated with FH (Hirayama T et al. J. Hum. Genet. 1998;43:250-4). In addition, this alteration is predicted to be deleterious by BayesDel 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	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.9	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;D
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		0.99
MutPred		0.98		Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);.;.;.;Gain of disorder (P = 0.0307);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
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

Other links and lift over

dbSNP: rs879254803; hg19: chr19-11222264;