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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:
RCV003581594.2

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
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004298311Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Feb 28, 2023) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed
See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298311.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

Last Updated: Oct 20, 2024