NM_000527.5(LDLR):c.679G>C (p.Asp227His) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 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:: RCV001366200.6

Allele description [Variation Report for NM_000527.5(LDLR):c.679G>C (p.Asp227His)]

NM_000527.5(LDLR):c.679G>C (p.Asp227His)

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.679G>C (p.Asp227His)

HGVS:

NC_000019.10:g.11105585G>C
NG_009060.1:g.21205G>C
NM_000527.5:c.679G>CMANE SELECT
NM_001195798.2:c.679G>C
NM_001195799.2:c.556G>C
NM_001195800.2:c.314-1807G>C
NM_001195803.2:c.314-980G>C
NP_000518.1:p.Asp227His
NP_001182727.1:p.Asp227His
NP_001182728.1:p.Asp186His
LRG_274:g.21205G>C
NC_000019.9:g.11216261G>C

Protein change:

D186H

Links:

dbSNP: rs2077282480

NCBI 1000 Genomes Browser:

rs2077282480

Molecular consequence:

NM_001195800.2:c.314-1807G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-980G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.679G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.679G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.556G>C - 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
SCV001562496	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17539906, 19467224, 21310417, 21382890, 22883975, 23375686, 23669246, 27680772, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001562496

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (9)
[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

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

An apparent inconsistency in parent to offspring transmission of point mutations of LDLR gene in familial hypercholesterolemia.

Rabacchi C, Wunsch A, Ghisellini M, Marino M, Pisciotta L, Bertolini S, Calandra S.

Clin Chim Acta. 2009 Aug;406(1-2):75-80. doi: 10.1016/j.cca.2009.05.017. Epub 2009 May 23.

PubMed [citation]

PMID:: 19467224

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV001562496.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

ClinVar contains an entry for this variant (Variation ID: 1057254). 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. 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. 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 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 aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 227 of the LDLR protein (p.Asp227His).

#	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: May 7, 2024

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