rs879254787

chr19-11111543-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000527.5(LDLR):c.1090T>C(p.Cys364Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,436 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 Conflicting classifications of pathogenicity (no stars). 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. C364G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:2
• 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 11 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr19-11111543-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2514788.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 19-11111543-T-C is Pathogenic according to our data. Variant chr19-11111543-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251657.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, Likely_pathogenic=1, Uncertain_significance=2}. Variant chr19-11111543-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.1090T>C	p.Cys364Arg	missense_variant	8/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1090T>C	p.Cys364Arg	missense_variant	8/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251338 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461436 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:2

Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 03, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
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	-	- -
Uncertain significance, 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 replaces cysteine with arginine at codon 364 in the EGF-like repeat B of the LDLR protein. This variant is also known as p.Cys343Arg in the mature 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). Experimental studies with cells from a patient carrying both this variant and p.Cys352Tyr in trans showed 15-30% LDLR activity (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 10978268, 15556094, 23064986, 25461735, 31345425, 34037665). This variant has also been observed in homozygous state in two individuals affected with severe homozygous familial hypercholesterolemia (PMID: 27940769, 37119068). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 10978268). This variant has been identified in 1/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys364Tyr, is considered to be disease-causing (ClinVar variation ID: 369852), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Familial hypercholesterolemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2023	This missense variant replaces cysteine with arginine at codon 364 in the EGF-like repeat B of the LDLR protein. This variant is also known as p.Cys343Arg in the mature 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). Experimental studies with cells from a patient carrying both this variant and p.Cys352Tyr in trans showed 15-30% LDLR activity (PMID: 1301956). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 10978268, 15556094, 23064986, 25461735, 31345425, 34037665). This variant has also been observed in homozygous state in two individuals affected with severe homozygous familial hypercholesterolemia (PMID: 27940769, 37119068). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 10978268). This variant has been identified in 1/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys364Tyr, is considered to be disease-causing (ClinVar variation ID: 369852), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Cys364Arg variant in LDLR has been reported in at least individuals with familial hypercholesterolemia, segregated with disease in 7 affected relatives from 2 families (PMID: 27940769, 23064986, 21722902, 1301956, 15556094, 11196104, 16314194, 21310417, 10978268, 25461735), and has been identified in 0.003% (1/34590) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP {dbSNPrsNumber}). This variant has also been reported in ClinVar (Variation ID#: 251657). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Cys364Arg variant may slightly impact protein function (PMID: 13019560). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual homozygous for this variant is highly specific for familial hypercholesterolemia based on the more severe phenotype and early onset of symptoms (PMID: 27940769). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based on the number of affected probands with the variant and evidence of co-segregation with the disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 18, 2023	This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 10978268, 15556094, 16314194, 21722902, 23375686, 25461735, 26723464). ClinVar contains an entry for this variant (Variation ID: 251657). 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. This variant disrupts the p.Cys343 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11196104, 21310417, 28379029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 364 of the LDLR protein (p.Cys364Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2022	Variant summary: LDLR c.1090T>C (p.Cys364Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251538 control chromosomes. c.1090T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Bertolini_2000, Laurie_2004, Cefalu_2001). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 09, 2017	p.Cys364Arg (c.1090T>C) in exon 8 of the LDLR gene (NM_000527.4) Given the strong case data and its rarity in the general population, we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 16 unrelated cases of familial hypercholesterolemia (FH) (not including this patient's family). There is strong case data. This variant is present in ClinVar and is classified as likely pathogenic by one lab, LDLR-LOVD, British Heart Foundation Study. They have seen it in 3 individuals. This variant was found in 2 of 108 Mexican patients (Robles-Osorio et al 2005, Vaca et al 2011), 1 out of 642 Brazilian patients (Jannes et al 2015), 1 out of 60 patients from archived samples (Laurie and George 2009), 1 out of 526 Welsh patients (Haralambos et al 2012) and 7 of 725 unrelated Italian patients from 2 families (Bertolini et al 2000). A 7-year-old boy with severe FH (LDL in the 900s) had 2 copies of this variant. His parents were first cousins (Grego et al 2016). This variant is located in the EGF homology domain, which is important for ligand binding function (Davis et al, 1987). Ambry's internal structural analysis team predicts that this variant disrupts a cysteine-cysteine bridge known to be integral to structural stability of the domain. The cysteine at codon 364 is completely conserved across species, and neighboring amino acids are also highly conserved. Other variants have been reported in association with disease at this codon (p.Cys364Tyr, p.Cys364Ser) and nearby codons (p.Gln359Ter, p.Gln359_Asp360del, p.Asp362Alafx, p.Gln366Ter, p.Gln366Arg, p.Gln366Pro, p.Leu367Valfs, p.Cys368Arg, p.Cys368Ser, p.Cys368Tyr, p.Cys368Ter). The variant was reported online in 1 of 123,080 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 12,790 individuals of Latino descent (MAF=0.003%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2023	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; Located within the LDL-receptor EGF precursor domain B, and participates in disulfide bonding with another cysteine residue which is critical for correct protein structure (Sudhof et al., 1985; Rudenko et al., 2002); Also denoted as p.(C343R) and FH Mexico-3 due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 35339733, 29874871, 1301956, 27940769, 21722902, 26723464, 10978268, 25461735, 16314194, 15556094, 19446849, 23064986, 31345425, 23375686, 32977124, 34037665) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2023

The p.C364R pathogenic mutation (also known as c.1090T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1090. The cysteine at codon 364 is replaced by arginine, an amino acid with highly dissimilar properties. 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 alteration has been detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 15-30% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66), and subsequent studies have reported this alteration in several individuals diagnosed with FH (Bertolini S et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-52). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 2 domain (Ambry internal data). In addition, alterations affecting the same amino acid position, p.C364F (c.1091G>T) and p.C364S (c.1091G>C), also have been described in patients with FH (Weiss N et al. J Inherit Metab Dis. 2000;23(8):778-90; Tichý L et al. Atherosclerosis. 2012;223(2):401-8). 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	0.52	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.6	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	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		0.96
MutPred		0.98		Gain of disorder (P = 0.0515);Gain of disorder (P = 0.0515);.;.;.;Gain of disorder (P = 0.0515);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
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: rs879254787; hg19: chr19-11222219;