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NM_000527.5(LDLR):c.325T>C (p.Cys109Arg) AND Hypercholesterolemia, familial, 1

Germline classification:
Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:
Jan 22, 2020
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:
RCV000237408.13

Allele description [Variation Report for NM_000527.5(LDLR):c.325T>C (p.Cys109Arg)]

NM_000527.5(LDLR):c.325T>C (p.Cys109Arg)

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.325T>C (p.Cys109Arg)
HGVS:
  • NC_000019.10:g.11105231T>C
  • NG_009060.1:g.20851T>C
  • NM_000527.5:c.325T>CMANE SELECT
  • NM_001195798.2:c.325T>C
  • NM_001195799.2:c.202T>C
  • NM_001195800.2:c.314-2161T>C
  • NM_001195803.2:c.314-1334T>C
  • NP_000518.1:p.Cys109Arg
  • NP_000518.1:p.Cys109Arg
  • NP_001182727.1:p.Cys109Arg
  • NP_001182728.1:p.Cys68Arg
  • LRG_274t1:c.325T>C
  • LRG_274:g.20851T>C
  • NC_000019.9:g.11215907T>C
  • NM_000527.4(LDLR):c.325T>C
  • NM_000527.4:c.325T>C
  • P01130:p.Cys109Arg
  • c.325T>C
Protein change:
C109R
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001701; UniProtKB: P01130#VAR_005316; dbSNP: rs140807148
NCBI 1000 Genomes Browser:
rs140807148
Molecular consequence:
  • NM_001195800.2:c.314-2161T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1334T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.325T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.325T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.202T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
12

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
SCV000294630LDLR-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,

SCV000322893Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 1, 2016)
germlineresearch

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

SCV000540726Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Nov 5, 2016)
inheritedclinical testing

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

SCV000583661U4M - 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]

SCV000606086Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
no assertion criteria provided
Pathogenicgermlineresearch

SCV000987037Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 11, 2018)
germlineclinical testing

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

SCV001422629Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 22, 2020)
germlinecuration

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch, curation
not providedgermlineyes137not provided4not providedclinical testing, research, literature only
Caucasianinheritedyes95not provided3964yesclinical testing

Citations

PubMed

Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico.

Robles-Osorio L, Huerta-Zepeda A, Ordóñez ML, Canizales-Quinteros S, Díaz-Villaseñor A, Gutiérrez-Aguilar R, Riba L, Huertas-Vázquez A, Rodríguez-Torres M, Gómez-Díaz RA, Salinas S, Ongay-Larios L, Codiz-Huerta G, Mora-Cabrera M, Mehta R, Gómez Pérez FJ, Rull JA, Rabès JP, Tusié-Luna MT, Durán-Vargas S, Aguilar-Salinas CA.

Arch Med Res. 2006 Jan;37(1):102-8. Erratum in: Arch Med Res. 2006 Feb;37(2):297.

PubMed [citation]
PMID:
16314194

Molecular characterization of familial hypercholesterolemia in German and Greek patients.

Dedoussis GV, Genschel J, Bochow B, Pitsavos C, Skoumas J, Prassa M, Lkhagvasuren S, Toutouzas P, Vogt A, Kassner U, Thomas HP, Schmidt H.

Hum Mutat. 2004 Mar;23(3):285-6.

PubMed [citation]
PMID:
14974088
See all PubMed Citations (7)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294630.2

#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 Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322893.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)
2not providednot providednot providednot providedresearch PubMed (2)

Description

"Compound Heterozygous (with p.(Asp354Gly)) patient fibroblast, 125I-LDL assays"

Description

0/190 non-FH alleles; 0/77 healthy control individuals

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided
2germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540726.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian9not providedyesclinical testing PubMed (2)

Description

Disrupt disulfide bridge between Cys109 and Cys121.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyes3964Whole bloodnot provided9not provided5not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583661.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided9not providednot providedclinical testing PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided9not provided7not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606086.1

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

From Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen, SCV000987037.1

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

Description

The mutation occurs at protein level at position 109 (position 88 of the mature protein) to exchange the amino acid cysteine for arginine. This change has already been described in the literature as FH Munster-1 allele, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. It leads to a strong reduction of LDL receptor activity. PMID: 11313767, 1301956

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422629.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (7)

Description

The p.Cys109Arg variant in LDLR has been reported in at least 7 individuals (including 2 Czech, 2 Portuguese, 1 Dutch, 1 German, and 1 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 16250003, 1301956, 16314194, 22698793, 24627126), and has been identified in 0.001771% (2/112906) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140807148). 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 has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 251156). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional missense variant (p.Cys109Ser) is likely pathogenic with a different amino acid change at the same position and has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (PMID: 12009418; Variation ID: 3743). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_Supporting, PS4_Moderate, PP3, PP1 (Richards 2015).

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

Last Updated: Oct 20, 2024