NM_000527.5(LDLR):c.523G>A (p.Asp175Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (11 submissions)
Last evaluated:: May 22, 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:: RCV000003924.22

Allele description [Variation Report for NM_000527.5(LDLR):c.523G>A (p.Asp175Asn)]

NM_000527.5(LDLR):c.523G>A (p.Asp175Asn)

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.523G>A (p.Asp175Asn)

Other names:

D154N; FH Afrikaner 3; FH Afrikaner-3

HGVS:

NC_000019.10:g.11105429G>A
NG_009060.1:g.21049G>A
NM_000527.5:c.523G>AMANE SELECT
NM_001195798.2:c.523G>A
NM_001195799.2:c.400G>A
NM_001195800.2:c.314-1963G>A
NM_001195803.2:c.314-1136G>A
NP_000518.1:p.Asp175Asn
NP_000518.1:p.Asp175Asn
NP_001182727.1:p.Asp175Asn
NP_001182728.1:p.Asp134Asn
LRG_274t1:c.523G>A
LRG_274:g.21049G>A
NC_000019.9:g.11216105G>A
NM_000527.4(LDLR):c.523G>A
NM_000527.4:c.523G>A
P01130:p.Asp175Asn
c.523G>A

Protein change:

D134N; ASP154ASN

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001755; UniProtKB: P01130#VAR_005326; OMIM: 606945.0044; dbSNP: rs121908033

NCBI 1000 Genomes Browser:

rs121908033

Molecular consequence:

NM_001195800.2:c.314-1963G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1136G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.400G>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

Recent activity

Clear Turn Off Turn On

tapasin-related protein isoform X2 [Tupaia chinensis]
tapasin-related protein isoform X2 [Tupaia chinensis]
gi|1561718117|ref|XP_027625024.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024089	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000268568	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jan 9, 2015)	germline	clinical testing
SCV000294768	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000503175	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]
SCV000583693	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]
SCV000606147	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000782949	Robarts Research Institute, Western University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000987518	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423090	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 2799589, 11845603, 1757095, 26342331, 25741868 Citation Link,
SCV002521080	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9104431, 25741868
SCV004848514	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 8, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24014831, 1757095, 7773731, 3430554, 1952806, 11845603, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	9	2	not provided	2602	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

The identification of two low-density lipoprotein receptor gene mutations in South African familial hypercholesterolaemia.

Kotze MJ, Langenhoven E, Warnich L, du Plessis L, Marx MP, Oosthuizen CJ, Retief AE.

S Afr Med J. 1989 Oct 21;76(8):399-401.

PubMed [citation]

PMID:: 2799589

Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): a reappraisal by using a resequencing approach.

Minicocci I, Prisco C, Montali A, Di Costanzo A, Ceci F, Pigna G, Arca M.

Atherosclerosis. 2015 Oct;242(2):618-24. doi: 10.1016/j.atherosclerosis.2015.06.036. Epub 2015 Jun 18.

PubMed [citation]

PMID:: 26342331

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000024089.1

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

Description

Graadt van Roggen et al. (1991) found a G-to-A transition in codon 154 resulting in substitution of asparagine for aspartic acid.

#	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 Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268568.1

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

From LDLR-LOVD, British Heart Foundation, SCV000294768.2

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

#	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

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503175.1

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

Description

subject mutated among 2600 FH index cases screened = 1, family member =1 /FH-Afrikaner-3 / 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		1	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583693.1

#	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	2	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606147.1

#	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 Robarts Research Institute, Western University, SCV000782949.1

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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987518.1

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423090.2

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

Description

The p.Asp175Asn variant in LDLR has been reported in over 15 individuals with Familial Hypercholesterolemia, segregated with disease in 10 affected relatives from 2 families (PMID: 1757095,11845603, 2799589; DOI: 10.4172/2327-5790.1000167), and has been identified in 0.01088% (2/18386) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908033). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant is a known founder variant in South Africa (PMID: 1757095). This variant has also been reported as a VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 3726). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based on the number of affected probands with the varianht and the segregation of this variant with FH. ACMG/AMP Criteria applied: PS4, PP1_strong, PP3 (Richards 2015).

#	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 3billion, SCV002521080.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003726). A different missense changes at the same codon (p.Asp175Tyr) has been reported to be associated with LDLR related disorder (ClinVar ID: VCV000251278 ). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848514.1

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

Description

The p.Asp175Asn variant in LDLR (also described as known as FH-3 alleles and p.Asp154Asn in the literature) is considered to be a founder variant in South Africa, that has been reported in multiple individuals with familial cholesterolemia (FH) and their affected relatives (Kotze 1987 PMID: 3430554, Kotze 1991 PMID: 1952806, Graadt van Roggen 1991 PMID: 1757095, Graadt van Roggen 1995 PMID: 7773731, Vergotine 2001 PMID: 11845603, Stein 2013 PMID: 24014831). This variant has also been reported by other clinical laboratories in ClinVar (Variantion ID: 3726) and has been identified in 0.01% (2/18386) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function by reducing LDLR activity (Graadt van Roggen 1995 PMID: 7773731) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_supporting, PP3.

#	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: Oct 20, 2024

Relating variation to medicine