rs746091400

Positions:

• chr19-11105597-T-C
• chr19-11105597-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.691T>C​(p.Cys231Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C231G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.92

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 disulfide_bond (size 15) in uniprot entity LDLR_HUMAN there are 56 pathogenic changes around while only 2 benign (97%) 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 chr19-11105597-T-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 19-11105597-T-C is Pathogenic according to our data. Variant chr19-11105597-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105597-T-C is described in Lovd as [Pathogenic]. Variant chr19-11105597-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.691T>C	p.Cys231Arg	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	c.691T>C	p.Cys231Arg	missense_variant	4/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2024	This missense variant replaces cysteine with arginine at codon 231 in the LDLR type A repeat 5 of the LDLR protein. This variant is also known as p.Cys210Arg 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 tools indicate that this variant has a deleterious impact on protein structure and function. An in vitro functional study has shown that this variant causes an approximately 40% reduction in LDLR binding and uptake (PMID: 19073363). This LDLR variant has been reported in three heterozygous individuals affected with familial hypercholesterolemia (PMID: 28964736, 34037665; ClinVar SCV001432574.1). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 19073363). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 19073363). Different variants affecting the same codon, p.Cys231Gly and p.Cys231Trp, are considered to be disease-causing (ClinVar variation ID: 251397, 251400), suggesting that cysteine at this position is important for LDLR protein function. This variant has not been identified 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	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Dec 05, 2018	- -

LDLR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2024

The LDLR c.691T>C variant is predicted to result in the amino acid substitution p.Cys231Arg. This amino acid position is also referred to as p.Cys210 using legacy nomenclature. This variant has been reported in the heterozygous and homozygous states in multiple individuals with hypercholesterolemia (Table 1, Wang et al. 2009. PubMed ID: 19073363; Table S2, Defesche et al. 2017. PubMed ID: 28964736; Table S1, Sturm et al. 2021. PubMed ID: 34037665). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Cys231Trp, p.Cys231Gly, and p.Cys231Tyr) have been reported in many individuals with hypercholesterolemia (Table 3, Marduel et al. 2010. PubMed ID: 20809525; Sundvold et al. 1996. PubMed ID: 8664907; Table 1, Shin et al. 2000. PubMed ID: 10782930). The c.691T>C (p.Cys231Arg) variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies using flow cytometry analysis demonstrate low LDL binding and internalization ability (PMID: 19073363); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as C210R; This variant is associated with the following publications: (PMID: 2988123, 12459547, 31447099, 34037665, 19073363) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2022

The p.C231R pathogenic mutation (also known as c.691T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 691. The cysteine at codon 231 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 alteration, which is also known as p.C210R, has been reported as homozygous in an individual with FH, being passed down from his affected parents (Wang L et al. Nutr Metab Cardiovasc Dis, 2009 Jul;19:391-400). This alteration has also been detected in FH cohorts (Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). Another alteration at the same codon, p.C231G (c.691T>G), has been described in multiple individuals with FH, and has been reported as commonly occurring in Norwegian FH cohorts (Sundvold H et al. Hum Mutat. 1996;7:70-1; Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Dušková L et al. Atherosclerosis. 2011;216:139-45; Tichý L et al. Atherosclerosis. 2012;223(2):401-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 231 of the LDLR protein (p.Cys231Arg). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys231 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 8664907, 10782930, 20809525), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Experimental studies have shown that this missense change affects LDLR function (PMID: 19073363). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251396). This variant is also known as C210R. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 19073363, 27830735). It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;T;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.8	H;.;.;H
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-11	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.91
MutPred		0.80		Loss of catalytic residue at V233 (P = 0.0729);Loss of catalytic residue at V233 (P = 0.0729);.;Loss of catalytic residue at V233 (P = 0.0729);
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		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

Other links and lift over

dbSNP: rs746091400; hg19: chr19-11216273;