NM_000527.5(LDLR):c.642G>A (p.Trp214Ter) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (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:: RCV000238519.4

Allele description [Variation Report for NM_000527.5(LDLR):c.642G>A (p.Trp214Ter)]

NM_000527.5(LDLR):c.642G>A (p.Trp214Ter)

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.642G>A (p.Trp214Ter)

Other names:

NM_000527.5(LDLR):c.642G>A; p.Trp214Ter

HGVS:

NC_000019.10:g.11105548G>A
NG_009060.1:g.21168G>A
NM_000527.5:c.642G>AMANE SELECT
NM_001195798.2:c.642G>A
NM_001195799.2:c.519G>A
NM_001195800.2:c.314-1844G>A
NM_001195803.2:c.314-1017G>A
NP_000518.1:p.Trp214Ter
NP_001182727.1:p.Trp214Ter
NP_001182728.1:p.Trp173Ter
LRG_274t1:c.642G>A
LRG_274:g.21168G>A
NC_000019.9:g.11216224G>A
NM_000527.4:c.642G>A
c.642G>A

Protein change:

W173*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001781; dbSNP: rs879254606

NCBI 1000 Genomes Browser:

rs879254606

Molecular consequence:

NM_001195800.2:c.314-1844G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1017G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.642G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.642G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.519G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000294839	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002506375	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Dec 13, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294839

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV002506375

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Pathogenic
(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	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	curation

Citations

PubMed

Spectrum of LDL receptor gene mutations in Denmark: implications for molecular diagnostic strategy in heterozygous familial hypercholesterolemia.

Jensen HK, Jensen LG, Meinertz H, Hansen PS, Gregersen N, Faergeman O.

Atherosclerosis. 1999 Oct;146(2):337-44.

PubMed [citation]

PMID:: 10532689

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294839.2

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506375.1

#	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.642G>A (p.Trp214Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 and 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: PVS1 - variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark. so PP4 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: Jan 13, 2025

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