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NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 27, 2024
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:
RCV002418071.3

Allele description [Variation Report for NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)]

NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)
Other names:
NP_000518.1:p.P699L; NM_000527.5(LDLR):c.2096C>T
HGVS:
  • NC_000019.10:g.11120478C>T
  • NG_009060.1:g.36098C>T
  • NM_000527.5:c.2096C>TMANE SELECT
  • NM_001195798.2:c.2096C>T
  • NM_001195799.2:c.1973C>T
  • NM_001195800.2:c.1592C>T
  • NM_001195803.2:c.1606+245C>T
  • NP_000518.1:p.Pro699Leu
  • NP_000518.1:p.Pro699Leu
  • NP_001182727.1:p.Pro699Leu
  • NP_001182728.1:p.Pro658Leu
  • NP_001182729.1:p.Pro531Leu
  • LRG_274t1:c.2096C>T
  • LRG_274:g.36098C>T
  • LRG_274p1:p.Pro699Leu
  • NC_000019.9:g.11231154C>T
  • NM_000527.4:c.2096C>T
  • P01130:p.Pro699Leu
  • c.2096C>T
Protein change:
P531L
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001600; UniProtKB: P01130#VAR_013955
Molecular consequence:
  • NM_001195803.2:c.1606+245C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.2096C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2096C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1973C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1592C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002726638Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Feb 27, 2024) 		germlineclinical testing

PubMed (33)
[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

Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia.

Thiart R, Scholtz CL, Vergotine J, Hoogendijk CF, de Villiers JN, Nissen H, Brusgaard K, Gaffney D, Hoffs MS, Vermaak WJ, Kotze MJ.

J Med Genet. 2000 Jul;37(7):514-9.

PubMed [citation]
PMID:
10882754
PMCID:
PMC1734636

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]
PMID:
11810272
See all PubMed Citations (33)

Details of each submission

From Ambry Genetics, SCV002726638.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (33)

Description

The p.P699L variant (also known as c.2096C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2096. The proline at codon 699 is replaced by leucine, an amino acid with similar properties. This variant, also known as p.P678L, has been reported in numerous familial hypercholesterolemia (FH) cohorts, though clinical details were limited in many of the studies (e.g., Thiart R et al. J. Med. Genet., 2000 Jul;37:514-9; Ahmad Z et al, Circ Cardiovasc Genet 2012 Dec; 5(6):666-75; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Kawame H et al. J Hum Genet, 2021 Jul;). This alteration has also been described in the compound heterozygous or homozygous state in multiple probands with homozygous FH (Schuster H et al, Arterioscler. Thromb. Vasc. Biol. 1995 Dec; 15(12):2176-80; Santos RD. Atheroscler Suppl, 2014 Sep;15:19-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Oct 13, 2024