NM_000527.5(LDLR):c.683_694del (p.Glu228_Cys231del) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 28, 2018
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:: RCV002365581.2

Allele description [Variation Report for NM_000527.5(LDLR):c.683_694del (p.Glu228_Cys231del)]

NM_000527.5(LDLR):c.683_694del (p.Glu228_Cys231del)

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.683_694del (p.Glu228_Cys231del)

HGVS:

NC_000019.10:g.11105589_11105600del
NG_009060.1:g.21209_21220del
NM_000527.5:c.683_694delMANE SELECT
NM_001195798.2:c.683_694del
NM_001195799.2:c.560_571del
NM_001195800.2:c.314-1803_314-1792del
NM_001195803.2:c.314-976_314-965del
NP_000518.1:p.Glu228_Cys231del
NP_001182727.1:p.Glu228_Cys231del
NP_001182728.1:p.Glu187_Cys190del
LRG_274t1:c.683_694del12
LRG_274:g.21209_21220del
NC_000019.9:g.11216263_11216274del
NC_000019.9:g.11216265_11216276del
NM_000527.4:c.683_694del12
NM_000527.4:c.683_694delAGGAAAACTGCG

Links:

dbSNP: rs1064792905

NCBI 1000 Genomes Browser:

rs1064792905

Molecular consequence:

NM_000527.5:c.683_694del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001195798.2:c.683_694del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001195799.2:c.560_571del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001195800.2:c.314-1803_314-1792del - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-976_314-965del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Gene ID:100219009

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002664280	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 28, 2018)	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

SCV002664280

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 28, 2018)

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 genetic background of an autosomal dominant hypercholesterolemia in the Czech Republic.

Tichý L, Fajkusová L, Zapletalová P, Schwarzová L, Vrablík M, Freiberger T.

Physiol Res. 2017 Apr 5;66(Suppl 1):S47-S54. Review.

PubMed [citation]

PMID:: 28379029

Details of each submission

From Ambry Genetics, SCV002664280.2

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

Description

The c.683_694del12 variant (also known as p.E228_C231del) is located in coding exon 4 of the LDLR gene. This variant results from an in-frame AGGAAAACTGCG deletion at nucleotide positions 683 to 694 at the end of exon 4. This results in the deletion of four amino acids between codons 228 and 231. This alteration has been reported in a cohort of subjects with familial hypercholesterolemia (Tichý L et al. Physiol Res, 2017 Apr;66:S47-S54). In addition, internal structural analysis indicates that this alteration both alters the conserved SDE triplet motif and disrupts a disulfide bond in the LDL type A repeat 5, which is important for ligand binding (Ambry internal data). Based on four different splice site prediction tools, this alteration is expected to create an in-frame alternate splice donor site at the new exon-intron boundary created by the deletion; however, experimental evidence is not currently available. Based on the majority of available evidence to date, this variant is likely to be 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: May 1, 2024

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