NM_000527.5(LDLR):c.97C>T (p.Gln33Ter) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (12 submissions)
Last evaluated:: Apr 30, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003868.24

Allele description [Variation Report for NM_000527.5(LDLR):c.97C>T (p.Gln33Ter)]

NM_000527.5(LDLR):c.97C>T (p.Gln33Ter)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.97C>T (p.Gln33Ter)

Other names:

Q12*; FH Turkey; FH Turkey/Milan-4; NM_000527.5(LDLR):c.97C>T; p.Gln33Ter

HGVS:

NC_000019.10:g.11100252C>T
NG_009060.1:g.15872C>T
NM_000527.5:c.97C>TMANE SELECT
NM_001195798.2:c.97C>T
NM_001195799.2:c.97C>T
NM_001195800.2:c.97C>T
NM_001195803.2:c.97C>T
NP_000518.1:p.Gln33Ter
NP_000518.1:p.Gln33Ter
NP_001182727.1:p.Gln33Ter
NP_001182728.1:p.Gln33Ter
NP_001182729.1:p.Gln33Ter
NP_001182732.1:p.Gln33Ter
LRG_274t1:c.97C>T
LRG_274:g.15872C>T
LRG_274p1:p.Gln33Ter
NC_000019.9:g.11210928C>T
NM_000527.4:c.97C>T
NM_000527.5:c.97C>T
c.97C>T
p.(Gln33*)
p.Gln33*

Protein change:

Q33*; GLN12TER

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001896; OMIM: 606945.0001

Molecular consequence:

NM_000527.5:c.97C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.97C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.97C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.97C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.97C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024033	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1988)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000294463	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 1301940, 15241806, 15701167, 2088165, 9974426 Citation Link,
SCV000503101	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583630	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000588484	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000606015	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607415	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000987040	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 7, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001653581	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301940, 24088637, 25487149, 28645073, 30710474, 32977124, 25741868
SCV002017112	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002506409	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Apr 30, 2022)	germline	curation	Citation Link,
SCV004820114	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 2088165, 18096825, 20809525, 21310417, 28235710, 28475941, 28645073, 31358055, 32759540, 33418990, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	51	20	not provided	2605	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research, curation
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Deletion in the first cysteine-rich repeat of low density lipoprotein receptor impairs its transport but not lipoprotein binding in fibroblasts from a subject with familial hypercholesterolemia.

Leitersdorf E, Hobbs HH, Fourie AM, Jacobs M, van der Westhuyzen DR, Coetzee GA.

Proc Natl Acad Sci U S A. 1988 Nov;85(21):7912-6.

PubMed [citation]

PMID:: 3263645
PMCID:: PMC282319

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, Pocoví M.

Hum Mutat. 2004 Aug;24(2):187.

PubMed [citation]

PMID:: 15241806

See all PubMed Citations (21)

Details of each submission

From OMIM, SCV000024033.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a homozygote with familial hypercholesterolemia (FHCL1; 143890) of Turkish ancestry, Leitersdorf and Hobbs (1990) identified a CAG-to-TAG change in codon 12 converting glutamine to a stop codon.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294463.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (5)
2	not provided	1	not provided	not provided	literature only	PubMed (5)
3	not provided	1	not provided	not provided	literature only	PubMed (5)
4	not provided	1	not provided	not provided	literature only	PubMed (5)
5	not provided	1	not provided	not provided	literature only	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503101.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	12	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 12 , family members = 6 with co-segregation

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		12	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583630.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	34	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

Description

ACMG Guidelines: Pathogenic (ii)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		34	not provided	20	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588484.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

%MAF(ExAC):0.001651

"Assay description:Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606015.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607415.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

%MAF(ExAC):0.001651

"Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen, SCV000987040.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653581.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002017112.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506409.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

NM_000527.5(LDLR):c.97C>T (p.Gln33Ter) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PS3, PS4, PM2, PP1 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). 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 perfomed 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 segregate with FH in at least 3 informatives meiosis (LDL-C > 75th percentile) from 1 family from CGMC, UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). In the same Laboratory segregation with FH was observed in 1 informative meiosis from 7 families. PP4 - Variant meets PM2 and is identified in 22 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004820114.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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