NM_000527.5(LDLR):c.259T>C (p.Trp87Arg) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 13, 2021
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:: RCV000508899.4

Allele description [Variation Report for NM_000527.5(LDLR):c.259T>C (p.Trp87Arg)]

NM_000527.5(LDLR):c.259T>C (p.Trp87Arg)

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.259T>C (p.Trp87Arg)

Other names:

NM_000527.5(LDLR):c.259T>C; p.Trp87Arg

HGVS:

NC_000019.10:g.11102732T>C
NG_009060.1:g.18352T>C
NM_000527.5:c.259T>CMANE SELECT
NM_001195798.2:c.259T>C
NM_001195799.2:c.190+2387T>C
NM_001195800.2:c.259T>C
NM_001195803.2:c.259T>C
NP_000518.1:p.Trp87Arg
NP_000518.1:p.Trp87Arg
NP_001182727.1:p.Trp87Arg
NP_001182729.1:p.Trp87Arg
NP_001182732.1:p.Trp87Arg
LRG_274t1:c.259T>C
LRG_274:g.18352T>C
LRG_274p1:p.Trp87Arg
NC_000019.9:g.11213408T>C
NM_000527.4:c.259T>C

Protein change:

W87R

Links:

dbSNP: rs121908025

NCBI 1000 Genomes Browser:

rs121908025

Molecular consequence:

NM_001195799.2:c.190+2387T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.259T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.259T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.259T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.259T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000606050	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV002506343	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Dec 13, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000606050

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

no assertion criteria provided

Pathogenic

germline

research

SCV002506343

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Dec 13, 2021)

germline

curation

Citation Link

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	research, curation

Details of each submission

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606050.1

#	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, SCV002506343.1

#	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.259T>C (p.Trp87Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5 and PP3) 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. PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) - Pathogenic by expert panel in ClinVar, so PM5 is met. PP3 - REVEL = 0.891. It is above 0.75, so PP3 is met.

#	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 5, 2023

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