NM_000527.5(LDLR):c.80G>A (p.Cys27Tyr) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 19, 2022
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:: RCV002580826.3

Allele description [Variation Report for NM_000527.5(LDLR):c.80G>A (p.Cys27Tyr)]

NM_000527.5(LDLR):c.80G>A (p.Cys27Tyr)

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.80G>A (p.Cys27Tyr)

HGVS:

NC_000019.10:g.11100235G>A
NG_009060.1:g.15855G>A
NM_000527.5:c.80G>AMANE SELECT
NM_001195798.2:c.80G>A
NM_001195799.2:c.80G>A
NM_001195800.2:c.80G>A
NM_001195803.2:c.80G>A
NM_001406861.1:c.338G>A
NP_000518.1:p.Cys27Tyr
NP_000518.1:p.Cys27Tyr
NP_001182727.1:p.Cys27Tyr
NP_001182728.1:p.Cys27Tyr
NP_001182729.1:p.Cys27Tyr
NP_001182732.1:p.Cys27Tyr
NP_001393790.1:p.Cys113Tyr
LRG_274t1:c.80G>A
LRG_274:g.15855G>A
LRG_274p1:p.Cys27Tyr
NC_000019.9:g.11210911G>A
NM_000527.4:c.80G>A

Protein change:

C113Y

Molecular consequence:

NM_000527.5:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.80G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406861.1:c.338G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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protein kinase C delta type isoform X1 [Rattus norvegicus]
protein kinase C delta type isoform X1 [Rattus norvegicus]
gi|2678902050|ref|XP_063131119.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002942448	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 19, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11668627, 14974088, 19026292, 25463123, 27497240, 7548065, 7603991, 7979249, 18325082, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002942448

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 19, 2022)

germline

clinical testing

PubMed (10)
[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

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent.

Wang J, Huff E, Janecka L, Hegele RA.

Hum Mutat. 2001 Oct;18(4):359.

PubMed [citation]

PMID:: 11668627

Molecular characterization of familial hypercholesterolemia in German and Greek patients.

Dedoussis GV, Genschel J, Bochow B, Pitsavos C, Skoumas J, Prassa M, Lkhagvasuren S, Toutouzas P, Vogt A, Kassner U, Thomas HP, Schmidt H.

Hum Mutat. 2004 Mar;23(3):285-6.

PubMed [citation]

PMID:: 14974088

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002942448.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Cys27 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11668627, 14974088, 19026292, 25463123, 27497240). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 27 of the LDLR protein (p.Cys27Tyr).

#	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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