NM_000527.5(LDLR):c.245G>T (p.Cys82Phe) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 3, 2018
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:: RCV002229813.6

Allele description [Variation Report for NM_000527.5(LDLR):c.245G>T (p.Cys82Phe)]

NM_000527.5(LDLR):c.245G>T (p.Cys82Phe)

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.245G>T (p.Cys82Phe)

HGVS:

NC_000019.10:g.11102718G>T
NG_009060.1:g.18338G>T
NM_000527.5:c.245G>TMANE SELECT
NM_001195798.2:c.245G>T
NM_001195799.2:c.190+2373G>T
NM_001195800.2:c.245G>T
NM_001195803.2:c.245G>T
NP_000518.1:p.Cys82Phe
NP_000518.1:p.Cys82Phe
NP_001182727.1:p.Cys82Phe
NP_001182729.1:p.Cys82Phe
NP_001182732.1:p.Cys82Phe
LRG_274t1:c.245G>T
LRG_274:g.18338G>T
LRG_274p1:p.Cys82Phe
NC_000019.9:g.11213394G>T
NM_000527.4:c.245G>T
c.245G>T

Protein change:

C82F

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000933; dbSNP: rs879254448

NCBI 1000 Genomes Browser:

rs879254448

Molecular consequence:

NM_001195799.2:c.190+2373G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.245G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.245G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.245G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.245G>T - 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
SCV000825602	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 3, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7548065, 7603991, 7979249, 18325082, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000825602

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 3, 2018)

germline

clinical testing

PubMed (5)
[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

Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain.

Bieri S, Djordjevic JT, Daly NL, Smith R, Kroon PA.

Biochemistry. 1995 Oct 10;34(40):13059-65.

PubMed [citation]

PMID:: 7548065

Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.

Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R.

Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6334-8.

PubMed [citation]

PMID:: 7603991
PMCID:: PMC41512

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000825602.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces cysteine with phenylalanine at codon 82 of the LDLR protein (p.Cys82Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypercholesterolemia (PMID:¬†12417285). This variant is also known in the literature as p.Cys61Phe. ClinVar contains an entry for this variant (Variation ID: 251093). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Cys82Gly, p.Cys82Tyr, p.Cys82Ser) in affected individuals suggests that this may be a clinically significant residue (PMID:¬†20809525,¬†11196104,¬†25461735). For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA 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: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082).

#	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: Jun 23, 2024

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