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NM_000527.5(LDLR):c.284G>T (p.Cys95Phe) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 1, 2021
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:
RCV002436071.2

Allele description [Variation Report for NM_000527.5(LDLR):c.284G>T (p.Cys95Phe)]

NM_000527.5(LDLR):c.284G>T (p.Cys95Phe)

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.284G>T (p.Cys95Phe)
HGVS:
  • NC_000019.10:g.11102757G>T
  • NG_009060.1:g.18377G>T
  • NM_000527.5:c.284G>TMANE SELECT
  • NM_001195798.2:c.284G>T
  • NM_001195799.2:c.190+2412G>T
  • NM_001195800.2:c.284G>T
  • NM_001195803.2:c.284G>T
  • NP_000518.1:p.Cys95Phe
  • NP_000518.1:p.Cys95Phe
  • NP_001182727.1:p.Cys95Phe
  • NP_001182729.1:p.Cys95Phe
  • NP_001182732.1:p.Cys95Phe
  • LRG_274t1:c.284G>T
  • LRG_274:g.18377G>T
  • LRG_274p1:p.Cys95Phe
  • NC_000019.9:g.11213433G>T
  • NM_000527.4:c.284G>T
  • c.284G>T
Protein change:
C95F
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000934; dbSNP: rs879254457
NCBI 1000 Genomes Browser:
rs879254457
Molecular consequence:
  • NM_001195799.2:c.190+2412G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.284G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.284G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.284G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.284G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002748161Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 1, 2021) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online.

Cenarro A, Jensen HK, Casao E, Civeira F, González-Bonillo J, Rodríguez-Rey JC, Gregersen N, Pocoví M.

Hum Mutat. 1998;11(5):413.

PubMed [citation]
PMID:
10206683

Eight novel LDL receptor gene mutations among patients under LDL apheresis in Dresden and Leipzig.

Bochmann H, Geisel J, Herrmann W, Purcz T, Reuter W, Julius U, Metzler W, Bergmann S, Jaross W, Gehrisch S.

Hum Mutat. 2001;17(1):76-7.

PubMed [citation]
PMID:
11139254
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV002748161.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The p.C95F pathogenic mutation (also known as c.284G>T), located in coding exon 3 of the LDLR gene, results from a G to T substitution at nucleotide position 284. The cysteine at codon 95 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This alteration, also known as p.C74F, has been reported in multiple FH cohorts (Van Gaal LF et al. Mol Cell Probes, 2001 Dec;15:329-36; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Ohta N et al. J Clin Lipidol Jan;10:547-555.e5; Bañares VG et al. J Clin Lipidol Feb;11:524-531). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Other alterations affecting the same amino acid. p.C95Y, p.C95S, p.S95R, p.C95G, have also been reported in association with FH (Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; (Bochmann H et al. Hum Mutat, 2001;17:76-7; Cenarro A et al. Hum Mutat, 1998;11:413). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 2 (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024