NM_000527.5(LDLR):c.557del (p.Gly186fs) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 10, 2020
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:: RCV000238378.4

Allele description [Variation Report for NM_000527.5(LDLR):c.557del (p.Gly186fs)]

NM_000527.5(LDLR):c.557del (p.Gly186fs)

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.557del (p.Gly186fs)

HGVS:

NC_000019.10:g.11105463del
NC_000019.9:g.11216136del
NG_009060.1:g.21083del
NM_000527.5:c.557delMANE SELECT
NM_001195798.2:c.557del
NM_001195799.2:c.434del
NM_001195800.2:c.314-1929del
NM_001195803.2:c.314-1102del
NP_000518.1:p.Gly186fs
NP_001182727.1:p.Gly186fs
NP_001182728.1:p.Gly145fs
LRG_274t1:c.557del
LRG_274:g.21083del
NC_000019.10:g.11105463delG
NC_000019.9:g.11216136del
NC_000019.9:g.11216139del
NC_000019.9:g.11216139delG
NM_000527.4:c.554delG
NM_000527.4:c.557delG
c.557delG

Protein change:

G145fs

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000649; dbSNP: rs879254573

NCBI 1000 Genomes Browser:

rs879254573

Molecular consequence:

NM_000527.5:c.557del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.557del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.434del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.314-1929del - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1102del - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000294790	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 11462246, 8882879, 9767373, 19446849 Citation Link,
SCV000536733	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Pathogenic (Aug 20, 2015)	germline	research	PubMed (3) [See all records that cite these PMIDs] 8882879, 11462246, 9767373
SCV004848347	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 10, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8882879, 9767373, 11462246, 19446849, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294790

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Pathogenic
(Mar 25, 2016)

germline

literature only

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000536733

Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq

no assertion criteria provided

Pathogenic
(Aug 20, 2015)

germline

research

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

SCV004848347

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 10, 2020)

germline

clinical testing

PubMed (5)
[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	yes	4	not provided	not provided	4	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Molecular genetics of familial hypercholesterolemia in Israel.

Reshef A, Nissen H, Triger L, Hensen TS, Eliav O, Schurr D, Safadi R, Gare M, Leitersdorf E.

Hum Genet. 1996 Nov;98(5):581-6.

PubMed [citation]

PMID:: 8882879

Mutations in the low-density lipoprotein receptor gene in Swedish familial hypercholesterolaemia patients: clinical expression and treatment response.

Ekström U, Abrahamson M, Wallmark A, Florén CH, Nilsson-Ehle P.

Eur J Clin Invest. 1998 Sep;28(9):740-7.

PubMed [citation]

PMID:: 9767373

See all PubMed Citations (5)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294790.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (4)
2	not provided	1	not provided	not provided	literature only	PubMed (4)
3	not provided	1	not provided	not provided	literature only	PubMed (4)
4	not provided	1	not provided	not provided	literature only	PubMed (4)

#	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
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536733.1

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

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848347.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Gly186fsX20 variant in LDLR has been reported in at least 2 heterozygous individuals and one compound heterozygous individual with hypercholesterolemia (Reshef 1996, Ekström 1998, Guardamagna 2009). It was absent from large population studies, but has been reported in ClinVar (Variation ID 251295). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 186 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.

#	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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