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:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294628	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 20145306, 11313767 Citation Link,
SCV000503139	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]
SCV000987024	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 11, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001440381	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003827136	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004830390	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 28, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11313767, 20145306, 34037665, 35741760, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	8	not provided	not provided	2602	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical 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

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

#	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
2	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, SCV000503139.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		6	not provided	not provided	not provided

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

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

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

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

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003827136.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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