rs140807148

chr19-11105231-T-Cchr19-11105231-T-G

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.325T>C(p.Cys109Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,076 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C109F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 4.99

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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 chr19-11105232-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 19-11105231-T-C is Pathogenic according to our data. Variant chr19-11105231-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251156.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=5, Uncertain_significance=1}. Variant chr19-11105231-T-C is described in Lovd as [Pathogenic]. Variant chr19-11105231-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.325T>C	p.Cys109Arg	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.325T>C	p.Cys109Arg	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250272 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135616

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461076 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	May 11, 2018	The mutation occurs at protein level at position 109 (position 88 of the mature protein) to exchange the amino acid cysteine for arginine. This change has already been described in the literature as FH Munster-1 allele, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. It leads to a strong reduction of LDL receptor activity. PMID: 11313767, 1301956 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	Disrupt disulfide bridge between Cys109 and Cys121. -
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	-	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/77 healthy control individuals -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Cys109Arg variant in LDLR has been reported in at least 7 individuals (including 2 Czech, 2 Portuguese, 1 Dutch, 1 German, and 1 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 16250003, 1301956, 16314194, 22698793, 24627126), and has been identified in 0.001771% (2/112906) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140807148). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 251156). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional missense variant (p.Cys109Ser) is likely pathogenic with a different amino acid change at the same position and has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (PMID: 12009418; Variation ID: 3743). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_Supporting, PS4_Moderate, PP3, PP1 (Richards 2015). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

LDLR: PS1, PM2, PM5, PP4, PS4:Supporting -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2021

The p.C109R pathogenic mutation (also known as c.325T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 325. The cysteine at codon 109 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, also known as FH Munster-1 or p.C88R, has been reported in individuals with familial hypercholesterolimia (FH) from a number of ethnic groups (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Robles-Osorio L et al. Arch Med Res. 2006;37:102-8; Tichý L et al. Atherosclerosis. 2012;223:401-8). A different nucleotide change resulting in the same amino acid alteration (c.324_325delGTinsTC) has also been detected in patients with FH (Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Chmara M et al. J Appl Genet. 2010;51:95-106). In addition, alterations at the same amino acid position, p.C109S and p.C109Y (also known as p.C88S and p.C88Y, respectively), have also been reported in association with FH (Pisciotta L et al. Biochim Biophys Acta. 2002;1587:7-11; Bertolini S et al. Atherosclerosis. 2013;227:342-8; Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Chmara M et al. J Appl Genet. 2010;51:95-106). 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

Invitae

Feb 28, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 109 of the LDLR protein (p.Cys109Arg). This variant is present in population databases (rs140807148, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 9544745, 11313767, 12009418, 14974088, 19843101, 20145306, 22698793, 32104752). This variant is also known as p.C88R. ClinVar contains an entry for this variant (Variation ID: 251156). 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 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.9	D;D;D;D
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.57
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
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: rs140807148; hg19: chr19-11215907;