NM_000527.5(LDLR):c.682del (p.Glu228fs) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 21, 2023
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:: RCV001382076.4

Allele description [Variation Report for NM_000527.5(LDLR):c.682del (p.Glu228fs)]

NM_000527.5(LDLR):c.682del (p.Glu228fs)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.682del (p.Glu228fs)

HGVS:

NC_000019.10:g.11105588del
NG_009060.1:g.21208del
NM_000527.5:c.682delMANE SELECT
NM_001195798.2:c.682del
NM_001195799.2:c.559del
NM_001195800.2:c.314-1804del
NM_001195803.2:c.314-977del
NP_000518.1:p.Glu228fs
NP_000518.1:p.Glu228fs
NP_001182727.1:p.Glu228fs
NP_001182728.1:p.Glu187fs
LRG_274t1:c.682del
LRG_274:g.21208del
LRG_274p1:p.Glu228fs
NC_000019.9:g.11216264del
NC_000019.9:g.11216264delG
NM_000527.4:c.682del
c.682delG
p.Glu228Argfs*37

Protein change:

E187fs

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000104; dbSNP: rs879254640

NCBI 1000 Genomes Browser:

rs879254640

Molecular consequence:

NM_000527.5:c.682del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.682del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.559del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.314-1804del - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-977del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001580703	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28645073, 20809525, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001580703

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (3)
[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

Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene.

Jiang L, Benito-Vicente A, Tang L, Etxebarria A, Cui W, Uribe KB, Pan XD, Ostolaza H, Yang SW, Zhou YJ, Martin C, Wang LY.

Atherosclerosis. 2017 Aug;263:163-170. doi: 10.1016/j.atherosclerosis.2017.06.014. Epub 2017 Jun 8.

PubMed [citation]

PMID:: 28645073

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001580703.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Glu228Argfs*37) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 20809525). ClinVar contains an entry for this variant (Variation ID: 251391). For these reasons, this variant has been classified as Pathogenic.

#	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 1, 2024

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