NM_000527.5(LDLR):c.346T>C (p.Cys116Arg) AND Familial hypercholesterolemia 1

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Mar 13, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000237774.3

Allele description [Variation Report for NM_000527.5(LDLR):c.346T>C (p.Cys116Arg)]

NM_000527.5(LDLR):c.346T>C (p.Cys116Arg)

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.346T>C (p.Cys116Arg)
Other names:
FH Alghero
HGVS:
  • NC_000019.10:g.11105252T>C
  • NG_009060.1:g.20872T>C
  • NM_000527.4:c.346T>C
  • NM_000527.5:c.346T>CMANE SELECT
  • NM_001195798.2:c.346T>C
  • NM_001195799.2:c.223T>C
  • NM_001195800.2:c.314-2140T>C
  • NM_001195803.2:c.314-1313T>C
  • NP_000518.1:p.Cys116Arg
  • NP_000518.1:p.Cys116Arg
  • NP_001182727.1:p.Cys116Arg
  • NP_001182728.1:p.Cys75Arg
  • LRG_274t1:c.346T>C
  • LRG_274:g.20872T>C
  • NC_000019.9:g.11215928T>C
  • P01130:p.Cys116Arg
  • c.346T>C
Protein change:
C116R
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000360; UniProtKB: P01130#VAR_005317; dbSNP: rs879254482
NCBI 1000 Genomes Browser:
rs879254482
Molecular consequence:
  • NM_001195800.2:c.314-2140T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1313T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.4:c.346T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.346T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.346T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.223T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial hypercholesterolemia 1 (FHCL1)
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000294642LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely pathogenic
(Mar 25, 2016)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000607450Fundacion Hipercolesterolemia Familiar - SAFEHEARTcriteria provided, single submitter
Pathogenic
(Mar 1, 2016)
germlineresearch

PubMed (2)
[See all records that cite these PMIDs]

SCV000816330Invitaecriteria provided, single submitter
Pathogenic
(Mar 13, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot provided2not providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (9)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294642.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (2)
2not provided1not providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607450.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)
2not providednot providednot providednot providedresearch PubMed (2)

Description

"Heterologous cells (CHO), FACS assays"
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000816330.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces cysteine with arginine at codon 116 of the LDLR protein (p.Cys116Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individuals affected with Familial Hypercholesterolemia (FH) (PMID: 11668640, 10634824), and in several other individuals collected as part of FH cohorts. However, it was unclear if the phenotype of these individuals met FH diagnostic thresholds (PMID: 10206683, 23375686, 15241806).  This variant is also known as C95R in the literature. ClinVar contains an entry for this variant (Variation ID: 251163). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain 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: 3495735, 4750422). In addition, missense substitutions within the LDLR EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Experimental studies have shown that this missense change affects the binding ability of the LDLR protein (PMID:  25545329). 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: Aug 29, 2020

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