NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Apr 29, 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:: RCV000238517.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg)]

NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg)

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.1447T>C (p.Trp483Arg)

Other names:

NM_000527.5(LDLR):c.1447T>C

HGVS:

NC_000019.10:g.11113623T>C
NG_009060.1:g.29243T>C
NM_000527.5:c.1447T>CMANE SELECT
NM_001195798.2:c.1447T>C
NM_001195799.2:c.1324T>C
NM_001195800.2:c.943T>C
NM_001195803.2:c.1066T>C
NP_000518.1:p.Trp483Arg
NP_000518.1:p.Trp483Arg
NP_001182727.1:p.Trp483Arg
NP_001182728.1:p.Trp442Arg
NP_001182729.1:p.Trp315Arg
NP_001182732.1:p.Trp356Arg
LRG_274t1:c.1447T>C
LRG_274:g.29243T>C
LRG_274p1:p.Trp483Arg
NC_000019.9:g.11224299T>C
NM_000527.4:c.1447T>C
P01130:p.Trp483Arg
c.1447T>C

Protein change:

W315R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001430; UniProtKB: P01130#VAR_005392; dbSNP: rs879254905

NCBI 1000 Genomes Browser:

rs879254905

Molecular consequence:

NM_000527.5:c.1447T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1447T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1324T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.943T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1066T>C - 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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Gene ID:118091247

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ST6GALNAC4 [Zootoca vivipara]
Gene ID:118077773

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295437	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16250003, 9039985 Citation Link,
SCV000606429	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001432633	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 4, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV004022413	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Apr 29, 2023)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	3	not provided	literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation

Citations

PubMed

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

Identification of a common low density lipoprotein receptor mutation (R329X) in the south of England: complete linkage disequilibrium with an allele of microsatellite D19S394.

Day IN, Haddad L, O'Dell SD, Day LB, Whittall RA, Humphries SE.

J Med Genet. 1997 Feb;34(2):111-6.

PubMed [citation]

PMID:: 9039985
PMCID:: PMC1050862

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295437.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	PubMed (2)

#	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
2	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, SCV000606429.1

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432633.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022413.1

#	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.1447T>C (p.Trp483Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting) 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 = 0.914. It is above 0.75, so PP3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases (1 index case with Simon-Broome/DLCN criteria of definite FH (LDL=12,4 mmol/L and tendinous xanthomas) from Ireland (PMID 8535447); 3 index case with Simon-Broome criteria of possible FH from UK (PMID 17539906); 1 index case with FH criteria (LDL-C >95th percentile and AD inheritance pattern of hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease) from The Netherlands (PMID 21382890), so PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in at least one index case who fulills clinical criteria for FH (see PS4 for details), 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: Sep 29, 2024

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