NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Jun 29, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000237895.12

Allele description [Variation Report for NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp)]

NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp)

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.1118G>A (p.Gly373Asp)

Other names:

FH Potenza-2

HGVS:

NC_000019.10:g.11111571G>A
NG_009060.1:g.27191G>A
NM_000527.5:c.1118G>AMANE SELECT
NM_001195798.2:c.1118G>A
NM_001195799.2:c.995G>A
NM_001195800.2:c.614G>A
NM_001195803.2:c.737G>A
NP_000518.1:p.Gly373Asp
NP_000518.1:p.Gly373Asp
NP_001182727.1:p.Gly373Asp
NP_001182728.1:p.Gly332Asp
NP_001182729.1:p.Gly205Asp
NP_001182732.1:p.Gly246Asp
LRG_274t1:c.1118G>A
LRG_274:g.27191G>A
LRG_274p1:p.Gly373Asp
NC_000019.9:g.11222247G>A
NM_000527.4:c.1118G>A
P01130:p.Gly373Asp
c.1118G>A
p.(Gly373Asp)

Protein change:

G205D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000320; UniProtKB: P01130#VAR_072845

Molecular consequence:

NM_000527.5:c.1118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.995G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000295229	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 11810272, 11933210, 15241806, 9974426 Citation Link,
SCV000503300	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]
SCV000583791	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]
SCV000588555	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 (1) [See all records that cite this PMID]
SCV000606332	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607560	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000748096	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001653621	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 (6) [See all records that cite these PMIDs] 9974426, 23375686, 30586733, 32977124, 33258288, 25741868
SCV004848515	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jun 29, 2021)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 30586733, 15241806, 21382890, 23375686, 9974426, 25461735, 28958694, 11810272, 11933210, 30270055, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	yes	16	6	not provided	2604	not provided	clinical testing, literature only
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features.

Bertolini S, Calandra S, Arca M, Averna M, Catapano AL, Tarugi P; Italian Study Group of Homozygous Familial Hypercholesterolemia.

Atherosclerosis. 2020 Nov;312:72-78. doi: 10.1016/j.atherosclerosis.2020.08.027. Epub 2020 Sep 9.

PubMed [citation]

PMID:: 32977124

Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Quaio CRDC, Moreira CM, Novo-Filho GM, Sacramento-Bobotis PR, Groenner Penna M, Perazzio SF, Dutra AP, da Silva RA, Santos MNP, de Arruda VYN, Freitas VG, Pereira VC, Pintao MC, Fornari ARDS, Buzolin AL, Oku AY, Burger M, Ramalho RF, Marco Antonio DS, E Ferreira EN, Pereira OJE, Cantagalli VD, et al.

Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):955-964. doi: 10.1002/ajmg.c.31860. Epub 2020 Nov 30.

PubMed [citation]

PMID:: 33258288

See all PubMed Citations (13)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295229.2

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

#	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

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503300.1

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

Description

subjects mutated among 2600 FH index cases screened = 3 / FH-Potenza-2 / Software predictions: 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		3	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583791.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Probable 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		9	not provided	6	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588555.1

#	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	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, SCV000606332.1

#	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, SCV000607560.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Iberoamerican FH Network, SCV000748096.1

#	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	unknown	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, SCV001653621.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (6)

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848515.1

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

Description

The p.Gly373Asp variant in LDLR, also described as p.Gly352Asp in the literature, has been previously reported in >15 individuals with hypercholesterolemia, including 1 individual with familial hypercholesterolemia (FH) and tendon xanthoma who was homozygous for the variant, and segregated in at least 1 affected family member (Bertolini 1999 PMID: 9974426, Fouchier 2001 PMID: 11810272, Salazar 2002 PMID: 11933210, Mozas 2004 PMID: 15241806, van der Graaf 2011 PMID: 21382890, Bertolini 2013 PMID: 23375686, Jannes 2015 PMID: 25461735, Scicali 2017 PMID: 28958694, Corral 2018 PMID: 30270055). It has also been reported in 1 individual with early onset myocardial infarction (Khera 2019 PMID: 30586733). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 251673) and has been identified in 0.0004% (1/282736) of pan-ethnic chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis support an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PM3_supporting.

#	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

Last Updated: Sep 29, 2024

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