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NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) AND Hypercholesterolemia, familial, 1

Germline classification:
Likely pathogenic (4 submissions)
Last evaluated:
Apr 28, 2023
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:
RCV000237444.6

Allele description [Variation Report for NM_000527.5(LDLR):c.298G>A (p.Asp100Asn)]

NM_000527.5(LDLR):c.298G>A (p.Asp100Asn)

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.298G>A (p.Asp100Asn)
Other names:
NM_000527.5(LDLR):c.298G>A
HGVS:
  • NC_000019.10:g.11102771G>A
  • NG_009060.1:g.18391G>A
  • NM_000527.5:c.298G>AMANE SELECT
  • NM_001195798.2:c.298G>A
  • NM_001195799.2:c.190+2426G>A
  • NM_001195800.2:c.298G>A
  • NM_001195803.2:c.298G>A
  • NP_000518.1:p.Asp100Asn
  • NP_000518.1:p.Asp100Asn
  • NP_001182727.1:p.Asp100Asn
  • NP_001182729.1:p.Asp100Asn
  • NP_001182732.1:p.Asp100Asn
  • LRG_274t1:c.298G>A
  • LRG_274:g.18391G>A
  • LRG_274p1:p.Asp100Asn
  • NC_000019.9:g.11213447G>A
  • NM_000527.4:c.298G>A
  • c.298G>A
Protein change:
D100N
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001686; dbSNP: rs879254459
NCBI 1000 Genomes Browser:
rs879254459
Molecular consequence:
  • NM_001195799.2:c.190+2426G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000294587LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Likely pathogenic
(Mar 25, 2016) 		germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000503126Centre 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) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000583648U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 30, 2017) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004022465ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)		Likely pathogenic
(Apr 28, 2023) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes41not provided2602not providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]
PMID:
15199436

Rare intracranial cholesterol deposition and a homozygous mutation of LDLR in a familial hypercholesterolemia patient.

Li H, Zhang Y, Wei X, Peng Y, Yang P, Tan H, Chen C, Pan Q, Liang D, Wu L.

Gene. 2015 Sep 15;569(2):313-7. doi: 10.1016/j.gene.2015.04.071. Epub 2015 Apr 29.

PubMed [citation]
PMID:
25936346
See all PubMed Citations (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294587.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (2)
2not provided1not providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot 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, SCV000503126.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / Software predictions: Damaging

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes2600not providednot provided1not providednot providednot provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583648.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not provided1not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022465.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP1, PP3, PP4, PS4_supporting 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: This variant is absent from gnomAD (gnomAD v2.1.1) - PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C=10.25 mmol/L ) as homozygous status, from PMID: 25936346. - PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID: 25936346 - PP3: REVEL = 0.93 - PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH from Ambry Genetics, after alternative causes for high cholesterol were excluded. - PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of possible FH from Ambry Genetics, 1 cases with Simon-Broome criteria of possible FH from PMID: 25936346)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024