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NM_000527.5(LDLR):c.6del (p.Trp4fs) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 30, 2022
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:
RCV002363055.2

Allele description [Variation Report for NM_000527.5(LDLR):c.6del (p.Trp4fs)]

NM_000527.5(LDLR):c.6del (p.Trp4fs)

Genes:
LDLR-AS1:LDLR antisense RNA 1 [Gene - HGNC]
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.6del (p.Trp4fs)
HGVS:
  • NC_000019.10:g.11089554del
  • NC_000019.9:g.11200227del
  • NG_009060.1:g.5174del
  • NM_000527.5:c.6delMANE SELECT
  • NM_001195798.2:c.6del
  • NM_001195799.2:c.6del
  • NM_001195800.2:c.6del
  • NM_001195803.2:c.6del
  • NP_000518.1:p.Trp4fs
  • NP_001182727.1:p.Trp4fs
  • NP_001182728.1:p.Trp4fs
  • NP_001182729.1:p.Trp4fs
  • NP_001182732.1:p.Trp4fs
  • LRG_274:g.5174del
  • NC_000019.9:g.11200227del
  • NC_000019.9:g.11200230del
  • NC_000019.9:g.11200230del
  • NC_000019.9:g.11200230delG
  • NM_000527.4:c.6delG
  • NM_000527.5:c.6del
  • NR_163945.1:n.109del
  • c.6delG
Protein change:
W4fs
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001825; dbSNP: rs875989888
NCBI 1000 Genomes Browser:
rs875989888
Molecular consequence:
  • NM_000527.5:c.6del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001195798.2:c.6del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001195799.2:c.6del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001195800.2:c.6del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001195803.2:c.6del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000527.5:c.6del - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195798.2:c.6del - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195799.2:c.6del - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195800.2:c.6del - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001195803.2:c.6del - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NR_163945.1:n.109del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002666758Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 30, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9.

Humphries SE, Neely RD, Whittall RA, Troutt JS, Konrad RJ, Scartezini M, Li KW, Cooper JA, Acharya J, Neil A.

Clin Chem. 2009 Dec;55(12):2153-61. doi: 10.1373/clinchem.2009.129759. Epub 2009 Oct 1.

PubMed [citation]
PMID:
19797716

Development of a high-resolution melting method for mutation detection in familial hypercholesterolaemia patients.

Whittall RA, Scartezini M, Li K, Hubbart C, Reiner Z, Abraha A, Neil HA, Dedoussis G, Humphries SE.

Ann Clin Biochem. 2010 Jan;47(Pt 1):44-55. doi: 10.1258/acb.2009.009076. Epub 2009 Oct 16.

PubMed [citation]
PMID:
19837725
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002666758.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The c.6delG pathogenic mutation, located in coding exon 1 of the LDLR gene, results from a deletion of one nucleotide at position 6, causing a translational frameshift with a predicted alternate stop codon (p.W4Gfs*202). This alteration has been previously reported in familial hypercholesterolemia cohorts (Hooper AJ et al. Atherosclerosis. 2012;224(2):430-4; Faiz F et al. Atherosclerosis. 2013;230(2):249-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024