NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (25 submissions)
Last evaluated:: Jun 9, 2021
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:: RCV000172964.47

Allele description [Variation Report for NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu)]

NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu)

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.1775G>A (p.Gly592Glu)

Other names:

FH Sicily; FH Foggia-1; FH Naples4; FH Sicilia-4; NP_000518.1:p.G592E; NM_000527.5(LDLR):c.1775G>A

HGVS:

NC_000019.10:g.11116928G>A
NG_009060.1:g.32548G>A
NM_000527.5:c.1775G>AMANE SELECT
NM_001195798.2:c.1775G>A
NM_001195799.2:c.1652G>A
NM_001195800.2:c.1271G>A
NM_001195803.2:c.1394G>A
NP_000518.1:p.Gly592Glu
NP_000518.1:p.Gly592Glu
NP_001182727.1:p.Gly592Glu
NP_001182728.1:p.Gly551Glu
NP_001182729.1:p.Gly424Glu
NP_001182732.1:p.Gly465Glu
LRG_274t1:c.1775G>A
LRG_274:g.32548G>A
LRG_274p1:p.Gly592Glu
NC_000019.9:g.11227604G>A
NM_000527.4:c.1775G>A
P01130:p.Gly592Glu
c.1775G>A
p.(Gly592Glu)

Protein change:

G424E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000237; UniProtKB: P01130#VAR_005403

Molecular consequence:

NM_000527.5:c.1775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1271G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1394G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)
- non-disruptive missense
variation affecting protein function [Variation Ontology: 0003]

Observations:

168

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
SCV000212140	Institute for Integrative and Experimental Genomics, University of Luebeck	criteria provided, single submitter (Submitter's publication)	Likely pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000268637	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Sep 7, 2010)	germline	clinical testing
SCV000295649	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (12) [See all records that cite these PMIDs] 11139254, 11641914, 1301956, 15241806, 15199436, 9654205, 20145306, 20506408, 17765246, 21310417, 23375686, 25463123 Citation Link,
SCV000322975	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 9974426, 21865347
SCV000484718	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000503412	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)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000540837	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation See additional submitters Centre of Molecular Biology and Gene Therapy, University Hospital Brno	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 5, 2016)	inherited	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25741868, 22698793, 11754108
SCV000583883	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]
SCV000588605	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 9974426, 21865347
SCV000606511	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607638	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 9974426, 21865347
SCV000748115	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 9974426, 21865347
SCV000778604	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 27, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000894177	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000987017	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 29, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000998546	UCSF Pediatric Lipid Clinic, University of California, San Francisco	criteria provided, single submitter (Submitter's publication)	Pathogenic	inherited	clinical testing
SCV001429254	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432593	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 3, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001653652	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1301956, 21865347, 23375686, 26723464, 28965616, 30710474, 31447099, 32977124, 32041611, 25741868
SCV001960930	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Pathogenic (Jun 9, 2021)	germline	curation	Citation Link,
SCV002538607	Laan Lab, Human Genetics Research Group, University of Tartu	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 1, 2021)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 35535697, 25741868
SCV002580733	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003827125	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003836115	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 29, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004822500	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (25) [See all records that cite these PMIDs] 1301956, 9654205, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21865347, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 26238499, 31947532, 35741760, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	48	1	not provided	2620	not provided	clinical testing, research, literature only
not provided	germline	unknown	14	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing, research
not provided	unknown	unknown	1	not provided	not provided	not provided	not provided	clinical testing, research
Caucasian	germline	yes	49	not provided	not provided	not provided	not provided	clinical testing
Caucasian	inherited	yes	277	166	not provided	3964	yes	clinical testing
European	inherited	yes	4	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction.

Brænne I, Kleinecke M, Reiz B, Graf E, Strom T, Wieland T, Fischer M, Kessler T, Hengstenberg C, Meitinger T, Erdmann J, Schunkert H.

Eur J Hum Genet. 2016 Feb;24(2):191-7. doi: 10.1038/ejhg.2015.100. Epub 2015 Jun 3.

PubMed [citation]

PMID:: 26036859
PMCID:: PMC4717192

Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia.

Huijgen R, Kindt I, Fouchier SW, Defesche JC, Hutten BA, Kastelein JJ, Vissers MN.

Hum Mutat. 2010 Jun;31(6):752-60. doi: 10.1002/humu.21258.

PubMed [citation]

PMID:: 20506408

See all PubMed Citations (37)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Institute for Integrative and Experimental Genomics, University of Luebeck, SCV000212140.1

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

#	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	1	not provided

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268637.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	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		3	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000295649.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (12)
2	not provided	1	not provided	not provided	literature only	PubMed (12)
3	not provided	1	not provided	not provided	literature only	PubMed (12)
4	not provided	1	not provided	not provided	literature only	PubMed (12)
5	not provided	1	not provided	not provided	literature only	PubMed (12)
6	not provided	1	not provided	not provided	literature only	PubMed (12)
7	not provided	1	not provided	not provided	literature only	PubMed (12)
8	not provided	1	not provided	not provided	literature only	PubMed (12)
9	not provided	1	not provided	not provided	literature only	PubMed (12)
10	not provided	1	not provided	not provided	literature only	PubMed (12)
11	not provided	1	not provided	not provided	literature only	PubMed (12)
12	not provided	1	not provided	not provided	literature only	PubMed (12)

#	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
6	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
9	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
10	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
11	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
12	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322975.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

%MAF (ExAC):0.004942

"Compound Heterozygous (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays; Heterologous cells (CHO), FACS assays; Heterozygous patients' Epstein-Barr virus transformed lymphocytes, FACS assays"

PubMed [ID: 9974426]

Description

0/220 non-FH alleles; 0/77 healthy control individuals

#	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
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Robarts Research Institute, Western University, SCV000484718.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	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	yes	not provided	not provided	not provided		4	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, SCV000503412.1

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

Description

subjects mutated among 2600 FH index cases screened = 11 , family members = 3 with co-segregation / previously described in association with FH, 5 to 15% LDLR Activity/software prediction damaging

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		11	not provided	not provided	not provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540837.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	277	not provided	yes	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3964	Whole blood	not provided		277	not provided	166	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583883.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#	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		5	not provided	3	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588605.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

%MAF(ExAC):0.004942

"Assay description:Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays"

PubMed [ID: 9974426]

#	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, SCV000606511.1

#	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, SCV000607638.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

%MAF(ExAC):0.004942

"Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays"

PubMed [ID: 9974426]

#	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 Iberoamerican FH Network, SCV000748115.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

%MAF(ExAC):0.004942

"Assay Description:Comp Htz (with p.(Cys89Arg) or with p.(Pro685Leu)) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays"

PubMed [ID: 9974426]

#	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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha, SCV000778604.1

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

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

From Fulgent Genetics, Fulgent Genetics, SCV000894177.1

#	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	unknown	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, SCV000987017.1

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

Description

This nucleotide substitution causes an exchange of the amino acid of glycine (Gly) to glutamic acid (Glu) p.Gly592Glu (legacy name: p.Gly571Glu). This change has already been described in the literature as FH Sicily, FH Foggia 1 and FH Naples 4 and has been found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It results in a reduced amount of biologically active LDL receptors on the cell surface. We observed this variant in a patient with TC up to 350 mg/dl and LDL-C approx 290 mg/dl at the age of 48 and in a patient with TC up to 300 mg/dl and LDL-C approx 250 mg/dl at the age of 5. PMID: 1301956, 27998977, 22390909, 26036859.

#	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 UCSF Pediatric Lipid Clinic, University of California, San Francisco, SCV000998546.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European	4	not provided	not provided	clinical testing	not provided

Description

The p.G592E variant in LDLR segregates with elevated level of LDL-C in a family of over ten individuals. The allele frequency of this variant in the population is 0.00004 based on the GnomAD database.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429254.4

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

Description

Criteria applied: PS4,PP1_STR,PS3_MOD,PM2,PP3

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

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432593.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	not provided	1	not provided	not provided	research	PubMed (2)
3	not provided	1	not provided	not provided	research	PubMed (2)
4	not provided	1	not provided	not provided	research	PubMed (2)
5	not provided	1	not provided	not provided	research	PubMed (2)
6	not provided	1	not provided	not provided	research	PubMed (2)
7	not provided	1	not provided	not provided	research	PubMed (2)
8	not provided	1	not provided	not provided	research	PubMed (2)

#	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
6	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653652.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	49	not provided	not provided	clinical testing	PubMed (10)

Description

Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.

#	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		49	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960930.1

#	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.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 239 index cases. PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%. PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).

#	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 Laan Lab, Human Genetics Research Group, University of Tartu, SCV002538607.1

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

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

From MGZ Medical Genetics Center, SCV002580733.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	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	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003827125.2

#	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 Baylor Genetics, SCV003836115.1

#	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	unknown	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, SCV004822500.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	PubMed (25)

Description

This missense variant (also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples) is located in the fifth LDLR type B repeat 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). A functional study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is 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		14	not provided	not provided	not provided

Last Updated: Oct 26, 2024

Relating variation to medicine