NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 29, 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:: RCV002229197.7

Allele description [Variation Report for NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)]

NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)

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.938G>A (p.Cys313Tyr)

HGVS:

NC_000019.10:g.11107512G>A
NG_009060.1:g.23132G>A
NM_000527.5:c.938G>AMANE SELECT
NM_001195798.2:c.938G>A
NM_001195799.2:c.815G>A
NM_001195800.2:c.434G>A
NM_001195803.2:c.557G>A
NP_000518.1:p.Cys313Tyr
NP_000518.1:p.Cys313Tyr
NP_001182727.1:p.Cys313Tyr
NP_001182728.1:p.Cys272Tyr
NP_001182729.1:p.Cys145Tyr
NP_001182732.1:p.Cys186Tyr
LRG_274t1:c.938G>A
LRG_274:g.23132G>A
LRG_274p1:p.Cys313Tyr
NC_000019.9:g.11218188G>A
NM_000527.4:c.938G>A
P01130:p.Cys313Tyr
c.938G>A

Protein change:

C145Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001871; UniProtKB: P01130#VAR_005358; dbSNP: rs875989911

NCBI 1000 Genomes Browser:

rs875989911

Molecular consequence:

NM_000527.5:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.815G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.434G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.557G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752418	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7548065, 7603991, 7979249, 18325082, 19318025, 9259195, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752418

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2018)

germline

clinical testing

PubMed (7)
[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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752418.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces cysteine with tyrosine at codon 313 of the LDLR protein (p.Cys313Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. 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). Other missense substitutions at this codon (p.Cys313Arg) have been reported in individuals affected with hypercholesterolemia (PMID: 19318025). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 9259195,¬†9698020, 11810272, 11857755). This variant is also known as p.Cys292Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 226339). This variant is not present in population databases (ExAC no frequency).

#	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

ClinVar

Relating variation to medicine