NM_000527.5(LDLR):c.233del (p.Arg78fs) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002523841.4

Allele description [Variation Report for NM_000527.5(LDLR):c.233del (p.Arg78fs)]

NM_000527.5(LDLR):c.233del (p.Arg78fs)

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.233del (p.Arg78fs)

HGVS:

NC_000019.10:g.11102706del
NG_009060.1:g.18326del
NM_000527.5:c.233delMANE SELECT
NM_001195798.2:c.233del
NM_001195799.2:c.190+2361del
NM_001195800.2:c.233del
NM_001195803.2:c.233del
NP_000518.1:p.Arg78fs
NP_000518.1:p.R78Lfs*127
NP_001182727.1:p.Arg78fs
NP_001182729.1:p.Arg78fs
NP_001182732.1:p.Arg78fs
LRG_274:g.18326del
NC_000019.10:g.11102706delG
NC_000019.9:g.11213382del
NM_000527.4:c.233delG
NM_000527.5:c.233delGMANE SELECT
p.(Arg78Leufs*128)

Protein change:

R78fs

Links:

dbSNP: rs1057516129

NCBI 1000 Genomes Browser:

rs1057516129

Molecular consequence:

NM_000527.5:c.233del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.233del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.233del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195803.2:c.233del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.190+2361del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Homo sapiens ribonuclease/angiogenin inhibitor 1 (RNH1), transcript variant 7, m...
Homo sapiens ribonuclease/angiogenin inhibitor 1 (RNH1), transcript variant 7, mRNA
gi|1675158151|ref|NM_203388.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003442659	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20809525, 28645073, 28492532
SCV005202241	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 30, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003442659

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 13, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005202241

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 30, 2024)

germline

clinical testing

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

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	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442659.2

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 369866). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg78Leufs*128) 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).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005202241.1

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

Description

Variant summary: LDLR c.233delG (p.Arg78LeufsX128) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251492 control chromosomes. c.233delG has been reported in the literature in at-least one individual affected with Familial Hypercholesterolemia (example: Wang_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27765764). ClinVar contains an entry for this variant (Variation ID: 369866). Based on the evidence outlined above, the variant was 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 29, 2024

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