NM_000527.5(LDLR):c.534T>G (p.Asp178Glu) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Apr 13, 2022
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:: RCV000237578.14

Allele description [Variation Report for NM_000527.5(LDLR):c.534T>G (p.Asp178Glu)]

NM_000527.5(LDLR):c.534T>G (p.Asp178Glu)

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.534T>G (p.Asp178Glu)

HGVS:

NC_000019.10:g.11105440T>G
NG_009060.1:g.21060T>G
NM_000527.5:c.534T>GMANE SELECT
NM_001195798.2:c.534T>G
NM_001195799.2:c.411T>G
NM_001195800.2:c.314-1952T>G
NM_001195803.2:c.314-1125T>G
NP_000518.1:p.Asp178Glu
NP_000518.1:p.Asp178Glu
NP_001182727.1:p.Asp178Glu
NP_001182728.1:p.Asp137Glu
LRG_274t1:c.534T>G
LRG_274:g.21060T>G
LRG_274p1:p.Asp178Glu
NC_000019.9:g.11216116T>G
NM_000527.4:c.534T>G
c.534T>G

Protein change:

D137E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000466; dbSNP: rs879254566

NCBI 1000 Genomes Browser:

rs879254566

Molecular consequence:

NM_001195800.2:c.314-1952T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1125T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.534T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.534T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.411T>G - 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
SCV000294780	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11196104, 17347910 Citation Link,
SCV000583698	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]
SCV000606152	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001365634	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jun 4, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11196104, 17347910, 28349240, 25741868
SCV002499683	Institute of Human Genetics, University Hospital Muenster	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002816928	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 12, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	4	1	not provided	2	not provided	clinical testing, literature only

Citations

PubMed

Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia.

Weiss N, Binder G, Keller C.

J Inherit Metab Dis. 2000 Dec;23(8):778-90.

PubMed [citation]

PMID:: 11196104

Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations.

Widhalm K, Dirisamer A, Lindemayr A, Kostner G.

J Inherit Metab Dis. 2007 Apr;30(2):239-47. Epub 2007 Mar 8.

PubMed [citation]

PMID:: 17347910

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294780.2

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

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583698.1

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

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606152.1

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365634.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Asp178Glu variant in LDLR (also reported at p.Asp157Glu in the literature) has been reported in at least 6 individuals with familial hypercholesterolemia (FH; Weiss 2000, Widhalm 2007, CCHMC pers comm., ClinVar Variation ID: 251287) and segregated with disease in 2 affected relatives from 1 family (CCHMC pers comm.). This variant was absent from large population studies. Computational prediction tools and conservation analyses are consistent with pathogenicity. Other variants at this position (p.Asp178Asn, p.Asn178Gly, p.Asn178His, p.Asn178Tyr, p.Asn178Val) have been reported in individuals with FH in the Human Gene Mutation Database (Stenson 2017) and in ClinVar, suggesting that changes at this position may not be tolerated. 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: PM2, PS4_Moderate, PP3, PM5_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

From Institute of Human Genetics, University Hospital Muenster, SCV002499683.1

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

Description

ACMG categories: PS5,PM1,PM2,PP2,PP5,BP1

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

From Fulgent Genetics, Fulgent Genetics, SCV002816928.1

#	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

Last Updated: Sep 29, 2024

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