rs879254667

chr19-11106631-A-Cchr19-11106631-A-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.761A>C(p.Gln254Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,872 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Q254E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 6.35

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 2 benign, 8 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 chr19-11106632-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251439.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 19-11106631-A-C is Pathogenic according to our data. Variant chr19-11106631-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11106631-A-C is described in Lovd as [Pathogenic]. Variant chr19-11106631-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.761A>C	p.Gln254Pro	missense_variant	5/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.761A>C	p.Gln254Pro	missense_variant	5/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:11

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Dec 19, 2018	The mutation at protein level leads to an amino acid exchange of glutamine to proline at position 254 (233rd amino acid of the mature protein) in the LDL receptor. This change has already been described in the literature as FH Reggio Emilia-2, as well as in patients with familial hypercholesterolaemia. We observed this variant in a patient with TC up to 360 mg/dl and LDL-C approx 300 mg/dl at the age of 55. PMID: 14974088, 11754108, 23375686 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Apr 03, 2024	We observed a heterozygous NM_000527:c.761A>C (p.Gln254Pro) genetic variant in the LDLR gene on WES data in a 56-y.o. female proband diagnosed with hypercholesterolemia and Brugada-like pattern on ECG. The c.761A>C (p.Gln254Pro) genetic variant in the LDLR gene is not observed at significant frequency in large population cohorts (gnomAD v4.0.0). ClinVar contains an entry for this variant (Variation ID: 251437) observed in patients with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 22698793, 23375686, 30415195). A functional study has shown that this variant does not affect protein expression at the cellular surface but reduces LDL binding and internalization activity by 80% compared to wild type protein (PMID: 31578082). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 26, 2019	The c.761A>C (p.Gln254Pro) variant in the LDLR gene has been described as FH Reggio Emilia-2 in the literature (PMID: 10978268) and reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 23375686, 23510778). This variant is absent from general population databases. Multiple lines of in silico algorithms have predicted this p.Gln254Pro change to be deleterious. Therefore, this c.761A>C (p.Gln254Pro) variant is classified as likely pathogenic. -
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 / previously described in association with FH / Software predictions: Conflicting -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 254 of the LDLR protein (p.Gln254Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 19319977, 19446849, 21925044, 25463123). This variant is also known as Q233P and FH Reggio Emilia-2. ClinVar contains an entry for this variant (Variation ID: 251437). 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.Gln233 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2019	This missense variant (also known as p.Gln233Pro in the mature protein and as FH-Reggio Emilia-2) replaces glutamine with proline at codon 254 in the LDLR type A repeat 6 of ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant does not affect protein expression at the cellular surface but reduces LDL binding and internalization activity by 80% compared to wild type protein (PMID: 31578082). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 22698793, 23375686, 30415195). 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 Pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 13, 2017

The p.Gln254Pro variant in LDLR has been reported in the heterozygous state in 9 individuals with familial hypercholesterolemia, as well as one homozygote (Bert olini 2000, Dedoussis 2004, Brusgaard 2006, Diakou 2011, Tichy 2012, Bertolini 2 013. In addition, this variant has been reported in a consanguineous family alon g with a second hypercholesterolemia variant (LDLRAP1 p.Gly136X). In this family , disease severity correlated with the various combinations of heterozygosity or homozygosity for the two variants (Soufi 2013). The p.Gln254Pro variant has als o been reported in ClinVar (Variation ID 251437) and was absent from large popul ation studies. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Gln254Pro variant is likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.761A>C (p.Q254P) alteration is located in exon 5 (coding exon 5) of the LDLR gene. This alteration results from an A to C substitution at nucleotide position 761, causing the glutamine (Q) at amino acid position 254 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals of various ethnic backgrounds with familial hypercholesterolemia (Bertolini, 2013; Kuhrová, 2002; Dedoussis, 2004; Brusgaard, 2006; Abifadel, 2009; Soufi, 2013; Mollaki, 2014). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in ligand binding and structure stability (Rudenko, 2002). Functional studies demonstrated reduced LDL binding and uptake (Banerjee, 2019). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in ligand binding and structure stability (Rudenko, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.92
MutPred		0.62		Gain of glycosylation at S252 (P = 0.0743);Gain of glycosylation at S252 (P = 0.0743);.;.;Gain of glycosylation at S252 (P = 0.0743);
MVP		1.0
MPC		0.89
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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: rs879254667; hg19: chr19-11217307;