NM_000527.5(LDLR):c.1433G>T (p.Gly478Val) 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:: RCV003021650.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1433G>T (p.Gly478Val)]

NM_000527.5(LDLR):c.1433G>T (p.Gly478Val)

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.1433G>T (p.Gly478Val)

HGVS:

NC_000019.10:g.11113609G>T
NG_009060.1:g.29229G>T
NM_000527.5:c.1433G>TMANE SELECT
NM_001195798.2:c.1433G>T
NM_001195799.2:c.1310G>T
NM_001195800.2:c.929G>T
NM_001195803.2:c.1052G>T
NP_000518.1:p.Gly478Val
NP_000518.1:p.Gly478Val
NP_001182727.1:p.Gly478Val
NP_001182728.1:p.Gly437Val
NP_001182729.1:p.Gly310Val
NP_001182732.1:p.Gly351Val
LRG_274t1:c.1433G>T
LRG_274:g.29229G>T
LRG_274p1:p.Gly478Val
NC_000019.9:g.11224285G>T
NM_000527.4:c.1433G>T

Protein change:

G310V

Molecular consequence:

NM_000527.5:c.1433G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1433G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1310G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.929G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1052G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV003315372	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17087781, 17765246, 21376320, 22353362, 23064986, 27206935, 30592178, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003315372

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (8)
[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

Identification and characterization of novel low-density lipoprotein receptor mutations of familial hypercholesterolaemia patients in Taiwan.

Charng MJ, Chiou KR, Chang HM, Cheng HM, Ye ZX, Lin SJ.

Eur J Clin Invest. 2006 Dec;36(12):866-74.

PubMed [citation]

PMID:: 17087781

Familial hypercholesterolaemia in Portugal.

Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK; Investigators of Portuguese FH Study..

Atherosclerosis. 2008 Feb;196(2):633-42. Epub 2007 Aug 31.

PubMed [citation]

PMID:: 17765246

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV003315372.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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 glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 478 of the LDLR protein (p.Gly478Val). 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. 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.Gly478 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17087781, 17765246, 21376320, 22353362, 23064986, 27206935, 30592178; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

#	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: Feb 28, 2024

ClinVar

Relating variation to medicine