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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 28, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003581594.1

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]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV004298311	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 28, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 1301956, 9544745, 11313767, 12009418, 14974088, 19843101, 20145306, 22698793, 32104752, 7548065, 7603991, 7979249, 18325082, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004298311

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 28, 2023)

germline

clinical testing

PubMed (14)
[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 genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Influence of genotype at the low density lipoprotein (LDL) receptor gene locus on the clinical phenotype and response to lipid-lowering drug therapy in heterozygous familial hypercholesterolaemia. The Familial Hypercholesterolaemia Regression Study Group.

Sun XM, Patel DD, Knight BL, Soutar AK.

Atherosclerosis. 1998 Jan;136(1):175-85.

PubMed [citation]

PMID:: 9544745

See all PubMed Citations (14)

Details of each submission

From Invitae, SCV004298311.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

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). This variant is present in population databases (rs140807148, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 9544745, 11313767, 12009418, 14974088, 19843101, 20145306, 22698793, 32104752). This variant is also known as p.C88R. ClinVar contains an entry for this variant (Variation ID: 251156). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. 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). 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

Last Updated: Jul 15, 2024

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