NM_000527.5(LDLR):c.665G>T (p.Cys222Phe) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 22, 2020
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:: RCV001376811.7

Allele description [Variation Report for NM_000527.5(LDLR):c.665G>T (p.Cys222Phe)]

NM_000527.5(LDLR):c.665G>T (p.Cys222Phe)

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.665G>T (p.Cys222Phe)

Other names:

NM_000527.5(LDLR):c.665G>T

HGVS:

NC_000019.10:g.11105571G>T
NG_009060.1:g.21191G>T
NM_000527.5:c.665G>TMANE SELECT
NM_001195798.2:c.665G>T
NM_001195799.2:c.542G>T
NM_001195800.2:c.314-1821G>T
NM_001195803.2:c.314-994G>T
NP_000518.1:p.Cys222Phe
NP_000518.1:p.Cys222Phe
NP_001182727.1:p.Cys222Phe
NP_001182728.1:p.Cys181Phe
LRG_274t1:c.665G>T
LRG_274:g.21191G>T
LRG_274p1:p.Cys222Phe
NC_000019.9:g.11216247G>T
NM_000527.4:c.665G>T
c.665G>T

Protein change:

C181F

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000788; dbSNP: rs730882086

NCBI 1000 Genomes Browser:

rs730882086

Molecular consequence:

NM_001195800.2:c.314-1821G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-994G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.665G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.665G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.542G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
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
SCV001573983	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 22, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11810272, 24671153, 27830735, 30526649, 7548065, 7603991, 7979249, 18325082, 25043216, 7573037, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001573983

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 22, 2020)

germline

clinical testing

PubMed (11)
[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

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

Functional characterization of two low-density lipoprotein receptor gene mutations in two Chinese patients with familial hypercholesterolemia.

Wang H, Xu S, Sun L, Pan X, Yang S, Wang L.

PLoS One. 2014;9(3):e92703. doi: 10.1371/journal.pone.0092703.

PubMed [citation]

PMID:: 24671153
PMCID:: PMC3966815

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001573983.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces cysteine with phenylalanine at codon 222 of the LDLR protein (p.Cys222Phe). 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 individual(s) with clinical features of familial hypercholesterolemia (PMID: 11810272, 24671153, 27830735, 30526649). ClinVar contains an entry for this variant (Variation ID: 251362). 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). This variant disrupts the p.Cys222 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 25043216, 7573037), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Sep 29, 2024

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