rs121908024

Positions:

• chr19-11100252-C-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PP4 PS3 PS4 PP1_Strong PM2 PVS1

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.97C>T (p.Gln33Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PVS1, PS3, PS4, PP1_Strong, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 25 March 2022.The supporting evidence is as follows:PM2 - PopMax MAF = 0.00001759 (0.002%) in European non-Finnish exomes (gnomAD v2.1.1).PVS1 - Variant leads to stop at codon 33, amino-terminal of amino acid 830.PS3 - Two studies contribute to PS3 attribution. One (PMID:2088165) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay performed on Heterologous cells (CHO-ldlA7). FACS, CLSM and WB results in 10% expression, binding and uptake of LDLR which is retained in the ER.PS4 - Variant meets PM2 and is identified in at least 10 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). 8 cases fulfil SB possible criteria and 14 fulfil DLCN >= 6 criteria.PP1_Strong- Variant segregates with phenotype in >6 informative meioses in >1 family [data from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière]: 14 affected family members have the variant.PP4 - Variant meets PM2 and is identified in 22 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023802/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 2.55

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 23 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.97C>T	p.Gln33*	stop_gained	2/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.97C>T	p.Gln33*	stop_gained	2/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251156 Hom.: 1 AF XY: 0.00 AC XY: 0 AN XY: 135732

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461424 Hom.: 1 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726996

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

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:12

Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 31, 2023	The c.97C>T (p.Gln33*) variant in the LDLR gene is located on the exon 2 and introduces a premature translation termination codon (p.Gln33*), resulting in an absent or disrupted protein product. The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 33418990, 28475941, 28235710, 32759540, 18096825). This variant segregates with FH phenotype in at least 3 informative meioses in 1 family and 1 informative meiosis in 7 families from different laboratories according to the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. Experimental study of LDLR expression with heterozygous and homozygous patient fibroblasts confirmed the negative functional impact of the variant (PMID: 2088165, 31358055, 28645073). The variant is reported in ClinVar (ID: 3683) and evaluated as pathogenic by the Expert Panel. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 21310417). This variant is rare in the general population according to gnomAD (2/251156). Therefore, the c.97C>T (p.Gln33*) variant of LDLR has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	ACMG Guidelines: Pathogenic (ii) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Dec 07, 2018	At protein level, the mutation leads to a premature termination of protein biosynthesis after 33 amino acids (12th amino acid of the mature protein). This change has already been described in the literature as FH Turkey and FH Milan-4, as well as in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. Most likely the mutation leads to a complete loss of LDL receptor activity due to premature degradation. PMID: 1301940, 15701167 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1988	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
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	subjects mutated among 2600 FH index cases screened = 12 , family members = 6 with co-segregation -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 25, 2022	NM_000527.5(LDLR):c.97C>T (p.Gln33Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PVS1, PS3, PS4, PP1_Strong, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 25 March 2022. The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001759 (0.002%) in European non-Finnish exomes (gnomAD v2.1.1). PVS1 - Variant leads to stop at codon 33, amino-terminal of amino acid 830. PS3 - Two studies contribute to PS3 attribution. One (PMID:2088165) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay performed on Heterologous cells (CHO-ldlA7). FACS, CLSM and WB results in 10% expression, binding and uptake of LDLR which is retained in the ER. PS4 - Variant meets PM2 and is identified in at least 10 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). 8 cases fulfil SB possible criteria and 14 fulfil DLCN >= 6 criteria. PP1_Strong- Variant segregates with phenotype in >6 informative meioses in >1 family [data from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière]: 14 affected family members have the variant. PP4 - Variant meets PM2 and is identified in 22 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 05, 2024	The LDLR c.97C>T (p.Gln33*) variant (also known as p.Q12X, FH-Turkey, and FH-Milan-4) causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) (PMIDs: 1301956 (1992), 15241806 (2004), 15701167 (2005), 18096825 (2008), 24085637 (2013), 28645073 (2017), 30710474 (2019), 32977124 (2020), 34037665 (2021), 35379577 (2022)), including cases of severe homozygous FH (PMIDs: 2088165 (1990), 9974426 (1999), 1301940 (1992), 27784735 (2016)). Additionally, it was shown to segregate with disease in one family (PMID: 15701167 (2005)). Experimental studies report this variant results in loss of protein function and proper LDL enzyme activity (PMIDs: 1301956 (1992), 28645073 (2017)). The frequency of this variant in the general population, 0.000008 (2/251156 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: reduced protein expression and impaired LDL binding and uptake (PMID: 28645073, 31358055); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Q12*), FH Turkey and FH Milan-4; This variant is associated with the following publications: (PMID: 9974426, 15701167, 32759540, 24088637, 25487149, 15241806, 1301940, 1301956, 32977124, 33740630, 34037665, 31358055, 28645073, 35379577, 30710474, 2088165) -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 09, 2017	p.Gln33* (also known as p.Gln12X in the literature) (c.97C>T) in the LDLR gene (NM_000527.4) Given that this variant truncates the LDL receptor, the very strong case data and the variant's rarity in large population databases, 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 25 unrelated cases of FH (not including this patient's family). There is strong cases data. This variant is listed in ClinVar and is classified as pathogenic by Invitae, LDL-LOVD British Heart Foundation (seen in 5 patients) and the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix (seen in 12 patients from 6 families out of 2600 index cases). Loux et al (1992, PMID1301940) found this variant (reported as p.Gln12*) in one of seven families with FH. The proband had homozygous FH, with total cholesterol levels in the 600s. Mozas et al (2004, PMID 15241806) found this variant in 2 out of 476 Spanish patients with FH. Zakharova et al (2005, PMID 15701167) found this variant in 2 out of 45 Russian patients (from the same family) with a clinical diagnosis of FH. Junyent et al (2008, PMID 18096825) found this variant in 2 of 146 Spanish patients. It is unclear whether or not these patients are related. Meng et al (2013, PMID 24088637) present a case report of a 12-year-old male with apparently Compound homozygous FH, and his father with heterozygous FH and the same variant. Sánchez-Hernández et al (2016, PMID 27784735) found this variant in 4 out of 97 patients: this variant was present in 2 patients in the homozygous form and 2 patient in the compound heterozygous form. Thirteen other variants at this and nearby codons (p.Glu28Ter, p.Arg29Ter, p.Glu31Ter, p.Glu31Lys, p.Glu31Aspfs, p.Phe32Cys, p.Gln33Hisfs, p.Cys34Gly, p.Cys34Ser, p.Cys34Ter, p.Gln35Ter, p.Asp36Glufs, p.Asp36Glu) are considered pathogenic in ClinVar. This variant is completely conserved across species and nearby residues are also strongly conserved. The variant is reported online 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. It is present in 1 European individual in the homozygous form out of 122,871 individuals in this database. 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. This variant was absent from 288 controls (Loux et al 1992; Junyent et al 2008) -

Familial hypercholesterolemia Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change creates a premature translational stop signal (p.Gln33*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs121908024, gnomAD 0.002%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301940, 15241806, 15701167, 18096825, 24088637, 27784735). This variant is also known as p.Gln12X. ClinVar contains an entry for this variant (Variation ID: 3683). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 24, 2023	This variant changes 1 nucleotide in exon 2 in the LDLR type A repeat 1 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study using transfected CHO-ldlA7 cells has shown that this variant causes a significant reduction in LDLR activity, LDL uptake, and LDL binding (PMID: 28645073). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 15241806, 15791167, 16250003, 18096825, 23375686, 34037665). This variant has also been observed in homozygous state in several individuals affected with severe homozygous familial hypercholesterolemia (PMID: 2088165, 1301940, 1301956, 9974426, 24088637, 27784735). This variant has been identified in 2/251156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2022

The p.Q33* pathogenic mutation (also known as c.97C>T), located in coding exon 2 of the LDLR gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration has been reported in association with familial hypercholesterolemia across various ethnicities (also reported as p.Q12X) (Hobbs HH, Annu. Rev. Genet. 1990 ; 24:133-70; Mozas P, Hum. Mutat. 2004 Aug; 24(2):187; Zakharova FM, BMC Med. Genet. 2005 Feb;6:6; Fouchier SW, Hum. Mutat. 2005 Dec; 26(6):550-6). This alteration was also reported in a homozygous state in two individuals who both had total cholesterol levels greater than 600 mg/dl (Loux N, Hum. Mutat. 1992;1(4):325-32; Meng X, Indian J Ophthalmol 2013 Dec; 61(12):770-1). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.82
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908024; hg19: chr19-11210928;