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NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) AND Hypercholesterolemia, familial, 1

Germline classification:
Conflicting interpretations of pathogenicity (9 submissions)
Last evaluated:
Mar 25, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000237262.12

Allele description [Variation Report for NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)]

NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)

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.542C>G (p.Pro181Arg)
HGVS:
  • NC_000019.10:g.11105448C>G
  • NG_009060.1:g.21068C>G
  • NM_000527.5:c.542C>GMANE SELECT
  • NM_001195798.2:c.542C>G
  • NM_001195799.2:c.419C>G
  • NM_001195800.2:c.314-1944C>G
  • NM_001195803.2:c.314-1117C>G
  • NP_000518.1:p.Pro181Arg
  • NP_000518.1:p.Pro181Arg
  • NP_001182727.1:p.Pro181Arg
  • NP_001182728.1:p.Pro140Arg
  • LRG_274t1:c.542C>G
  • LRG_274:g.21068C>G
  • LRG_274p1:p.Pro181Arg
  • NC_000019.9:g.11216124C>G
  • NM_000527.4:c.542C>G
  • c.542C>G
  • p.(Pro181Arg)
Protein change:
P140R
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000361; dbSNP: rs557344672
NCBI 1000 Genomes Browser:
rs557344672
Molecular consequence:
  • NM_001195800.2:c.314-1944C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1117C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.542C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.542C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.419C>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)
Observations:
3

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000294785LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

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

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000503179Centre 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 benign
(Dec 16, 2016)
germlineclinical testing

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

SCV000540742Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Nov 5, 2016)
unknownclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000583701U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 30, 2017)
germlineclinical testing

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

SCV000606153Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
no assertion criteria provided
Pathogenicgermlineresearch

SCV000839992Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Apr 25, 2018)
germlineclinical testing

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

SCV001653596Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(May 24, 2021)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004041648Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
no assertion criteria provided
Uncertain significance
(Oct 9, 2023)
germlineclinical testing

SCV004812136Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 25, 2024)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes61not provided2604not providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research
Caucasiangermlineyes2not providednot providednot providednot providedclinical testing
Caucasianunknownyes22not provided3964yesclinical testing

Citations

PubMed

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]
PMID:
16250003
See all PubMed Citations (11)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294785.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (4)
2not provided1not providednot providedliterature only PubMed (4)
3not provided1not providednot providedliterature only PubMed (4)
4not provided1not providednot providedliterature only PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided
4germlineyes1not 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, SCV000503179.1

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

Description

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting

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

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540742.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian2not providedyesclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyes3964Whole bloodnot provided2not provided2not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583701.1

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

Description

Dutch Lipid Clinic Scoring : Probable FH

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

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606153.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839992.1

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

Description

This c.542C>G (p.Pro181Arg) variant in the LDLR gene has been reported in multiple familial hypercholesterolaemia patients [PMID: 11600564, 11754108, 16250003, 23375686] than that observed as extremely low in general population according to gnomad database. Functional studies showed impairment of precursor LDLR with reduced penetrance associated with this variant [PMID: 21868016]. Multiple in silico predictions suggest this proline to arginine is deleterious. Based upon above evidences, c.542C>G (p.Pro181Arg) variant in the LDLR gene is classified as likely pathogenic.

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

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653596.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian2not providednot providedclinical testing PubMed (8)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004041648.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004812136.1

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

Description

Criteria applied: PS4_MOD,PM1,PM2_SUP_MOD,PM5,PP3,PP4

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

Last Updated: Jun 29, 2024