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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 17, 2023
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:: RCV001207725.7

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]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001379090	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 11313767, 14974088, 19843101, 20145306, 22698793, 7548065, 7603991, 7979249, 18325082, 1131376, 9544745, 12009418, 28492532
SCV004358473	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 503139, 987024, 11313767, 20145306, 34037665, 35741760, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001379090

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV004358473

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 17, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Mutation screening in patients for familial hypercholesterolaemia (ADH).

Taylor A, Patel K, Tsedeke J, Humphries SE, Norbury G.

Clin Genet. 2010 Jan;77(1):97-9. doi: 10.1111/j.1399-0004.2009.01279.x. Epub 2009 Oct 14. No abstract available.

PubMed [citation]

PMID:: 19843101

See all PubMed Citations (18)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001379090.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 109 of the LDLR protein (p.Cys109Arg). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 14974088, 19843101, 20145306, 22698793). ClinVar contains an entry for this variant (Variation ID: 251154). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 1131376, 9544745, 12009418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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 Color Diagnostics, LLC DBA Color Health, SCV004358473.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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