NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 28, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000237631.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys)]

NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys)

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.1449G>T (p.Trp483Cys)

Other names:

NM_000527.5(LDLR):c.1449G>T; p.Trp483Cys

HGVS:

NC_000019.10:g.11113625G>T
NG_009060.1:g.29245G>T
NM_000527.5:c.1449G>TMANE SELECT
NM_001195798.2:c.1449G>T
NM_001195799.2:c.1326G>T
NM_001195800.2:c.945G>T
NM_001195803.2:c.1068G>T
NP_000518.1:p.Trp483Cys
NP_000518.1:p.Trp483Cys
NP_001182727.1:p.Trp483Cys
NP_001182728.1:p.Trp442Cys
NP_001182729.1:p.Trp315Cys
NP_001182732.1:p.Trp356Cys
LRG_274t1:c.1449G>T
LRG_274:g.29245G>T
LRG_274p1:p.Trp483Cys
NC_000019.9:g.11224301G>T
NM_000527.4:c.1449G>T
c.1449G>T

Protein change:

W315C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001432; dbSNP: rs879254907

NCBI 1000 Genomes Browser:

rs879254907

Molecular consequence:

NM_000527.5:c.1449G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1449G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1326G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.945G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1068G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295441	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000606433	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004022408	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Apr 28, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295441

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Uncertain significance
(Mar 25, 2016)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000606433

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

no assertion criteria provided

Pathogenic

germline

research

SCV004022408

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Apr 28, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation

Citations

PubMed

The genetic spectrum of familial hypercholesterolemia in south-eastern Poland.

Sharifi M, Walus-Miarka M, Idzior-Waluś B, Malecki MT, Sanak M, Whittall R, Li KW, Futema M, Humphries SE.

Metabolism. 2016 Mar;65(3):48-53. doi: 10.1016/j.metabol.2015.10.018. Epub 2015 Nov 10.

PubMed [citation]

PMID:: 26892515
PMCID:: PMC4766367

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295441.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606433.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022408.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.951. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 1 index case with Simon Broome criteria from Poland (PMID 26892515), after alternative causes of high cholesterol were excluded.

#	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: Aug 13, 2023

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