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NM_000527.5(LDLR):c.324_325delinsTC (p.Cys109Arg) AND Hypercholesterolemia, familial, 1

Germline classification:
Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:
Jul 22, 2024
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:
RCV000237956.10

Allele description [Variation Report for NM_000527.5(LDLR):c.324_325delinsTC (p.Cys109Arg)]

NM_000527.5(LDLR):c.324_325delinsTC (p.Cys109Arg)

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
Indel
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.324_325delinsTC (p.Cys109Arg)
HGVS:
  • NC_000019.10:g.11105230_11105231delinsTC
  • NG_009060.1:g.20850_20851delinsTC
  • NM_000527.5:c.324_325delinsTCMANE SELECT
  • NM_001195798.2:c.324_325delinsTC
  • NM_001195799.2:c.201_202delinsTC
  • NM_001195800.2:c.314-2162_314-2161delinsTC
  • NM_001195803.2:c.314-1335_314-1334delinsTC
  • NP_000518.1:p.Cys109Arg
  • NP_001182727.1:p.Cys109Arg
  • NP_001182728.1:p.Cys68Arg
  • LRG_274:g.20850_20851delinsTC
  • NC_000019.9:g.11215906_11215907delinsTC
  • NM_000527.4:c.324_325delGTinsTC
  • NM_000527.5:c.324_325delinsTC
  • c.324_325delinsTC
Protein change:
C109R
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000050; dbSNP: rs879254476
NCBI 1000 Genomes Browser:
rs879254476
Molecular consequence:
  • NM_001195800.2:c.314-2162_314-2161delinsTC - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1335_314-1334delinsTC - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.324_325delinsTC - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.324_325delinsTC - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.201_202delinsTC - missense variant - [Sequence Ontology: SO:0001583]
Observations:
9

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
SCV000294628LDLR-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,

SCV000503139Centre 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]

SCV000987024Department 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]

SCV001440381Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 22, 2024)
unknownclinical testing

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

SCV003827136Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 16, 2022)
germlineclinical testing

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

SCV004830390All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 28, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes8not providednot provided2602not providedclinical testing, literature only
not providedgermlineunknown1not providednot provided108544not providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom.

Heath KE, Humphries SE, Middleton-Price H, Boxer M.

Eur J Hum Genet. 2001 Apr;9(4):244-52.

PubMed [citation]
PMID:
11313767

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]
PMID:
20145306
See all PubMed Citations (5)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294628.2

#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, SCV000503139.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testing PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 6 , family members = 6 with co-segregation

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes2600not providednot provided6not providednot providednot provided

From Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen, SCV000987024.1

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

Description

The deletion of the two nucleotides GT and the insertion of the two nucleotides TC at position 324 leads to the amino acid exchange cysteine to arginine (p.Cys109Arg). This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. We diagnosed this variant in a patient with FH at the age of 17. PMID: 11313767, 14974088, 16314194

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440381.2

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

Description

Criteria applied: PS1,PS4,PM5_STR,PM1,PM2

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

From Revvity Omics, Revvity, SCV003827136.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004830390.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

This missense variant deletes 2 nucleotides and inserts 2 nucleotides, resulting in the replacement of cysteine with arginine at codon 109 in the LDLR type A repeat 3 of the LDLR protein. This variant is also known as p.Cys88Arg in the mature protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11313767, 20145306, 34037665, 35741760; ClinVar SCV000503139.1 and SCV000987024.1). A different missense variant occurring at the same codon and causing the same amino acid change, c.325T>C (p.Cys109Arg), is known to be disease-causing (ClinVar variation ID: 251156). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Oct 20, 2024