NM_000527.5(LDLR):c.680A>T (p.Asp227Val) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 10, 2023
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:: RCV001066736.8

Allele description [Variation Report for NM_000527.5(LDLR):c.680A>T (p.Asp227Val)]

NM_000527.5(LDLR):c.680A>T (p.Asp227Val)

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.680A>T (p.Asp227Val)

HGVS:

NC_000019.10:g.11105586A>T
NG_009060.1:g.21206A>T
NM_000527.5:c.680A>TMANE SELECT
NM_001195798.2:c.680A>T
NM_001195799.2:c.557A>T
NM_001195800.2:c.314-1806A>T
NM_001195803.2:c.314-979A>T
NP_000518.1:p.Asp227Val
NP_000518.1:p.Asp227Val
NP_001182727.1:p.Asp227Val
NP_001182728.1:p.Asp186Val
LRG_274t1:c.680A>T
LRG_274:g.21206A>T
LRG_274p1:p.Asp227Val
NC_000019.9:g.11216262A>T
NM_000527.4:c.680A>T
c.680A>T

Protein change:

D186V

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001813; dbSNP: rs879254638

NCBI 1000 Genomes Browser:

rs879254638

Molecular consequence:

NM_001195800.2:c.314-1806A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-979A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.680A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.680A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.557A>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
SCV001231753	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 10, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 20809525, 17539906, 19467224, 21310417, 21382890, 22883975, 23375686, 23669246, 27680772, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001231753

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 10, 2023)

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

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia.

Taylor A, Tabrah S, Wang D, Sozen M, Duxbury N, Whittall R, Humphries SE, Norbury G.

Clin Genet. 2007 Jun;71(6):561-8.

PubMed [citation]

PMID:: 17539906

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001231753.5

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 227 of the LDLR protein (p.Asp227Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia in a family and has been indentified in individuals affected with this condition (PMID: 20809525; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 251388). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant disrupts the p.Asp227 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17539906, 19467224, 21310417, 21382890, 22883975, 23375686, 23669246, 27680772). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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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