19-11105267-T-C

Position:

• chr19-11105267-T-C

Variant summary

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

The ENST00000558518.6(LDLR):​c.361T>C​(p.Cys121Arg) 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. C121W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 10 uncertain in ENST00000558518.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11105268-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 19-11105267-T-C is Pathogenic according to our data. Variant chr19-11105267-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105267-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.361T>C	p.Cys121Arg	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.361T>C	p.Cys121Arg	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2020

The p.C121R variant (also known as c.361T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 361. The cysteine, located in LDLR class A repeat 3, at codon 121 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 cysteine alteration (also referred to as C100R) has been detected in an FH cohort; however, clinical details were limited (Alonso R et al. Clin Biochem, 2009 Jun;42:899-903). This variant also co-occurred with a second variant in LDLR in an individual with homozygous FH presentation (Klaus G et al. Pediatr Nephrol, 2018 07;33:1199-1208). A different variant affecting this codon (p.C121Y, c.362G>A) has been reported in association with FH (Cefalù AB et al. Int J Mol Med, 2006 Mar;17:539-46). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 3 (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 121 of the LDLR protein (p.Cys121Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 19318025; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 251174). 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%. 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). This variant disrupts the p.Cys121 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12417285, 16465405, 23375686), which suggests that this may be a clinically significant amino acid residue. 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	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.2	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-11	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.95		Loss of methylation at K120 (P = 0.0258);Loss of methylation at K120 (P = 0.0258);.;Loss of methylation at K120 (P = 0.0258);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
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: rs879254492; hg19: chr19-11215943;