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NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 3, 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:
RCV002399589.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)]

NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)

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.1576C>T (p.Pro526Ser)
Other names:
FH Cincinnati-3; NM_000527.5(LDLR):c.1576C>T
HGVS:
  • NC_000019.10:g.11113752C>T
  • NG_009060.1:g.29372C>T
  • NM_000527.5:c.1576C>TMANE SELECT
  • NM_001195798.2:c.1576C>T
  • NM_001195799.2:c.1453C>T
  • NM_001195800.2:c.1072C>T
  • NM_001195803.2:c.1195C>T
  • NP_000518.1:p.Pro526Ser
  • NP_000518.1:p.Pro526Ser
  • NP_001182727.1:p.Pro526Ser
  • NP_001182728.1:p.Pro485Ser
  • NP_001182729.1:p.Pro358Ser
  • NP_001182732.1:p.Pro399Ser
  • LRG_274t1:c.1576C>T
  • LRG_274:g.29372C>T
  • LRG_274p1:p.Pro526Ser
  • NC_000019.9:g.11224428C>T
  • NM_000527.4:c.1576C>T
  • P01130:p.Pro526Ser
  • c.1576C>T
Protein change:
P358S
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000076; UniProtKB: P01130#VAR_005396; dbSNP: rs730882106
NCBI 1000 Genomes Browser:
rs730882106
Molecular consequence:
  • NM_000527.5:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1453C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1072C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functional variant [Sequence Ontology: SO:0001536] - Comment(s)

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
SCV002710067Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(May 3, 2024) 		germlineclinical testing

PubMed (7)
[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

The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia.

Heath KE, Gudnason V, Humphries SE, Seed M.

Atherosclerosis. 1999 Mar;143(1):41-54.

PubMed [citation]
PMID:
10208479

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]
PMID:
11462246
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002710067.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The p.P526S pathogenic mutation (also known as c.1576C>T and p.P505S), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1576. The proline at codon 526 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals with familial hypercholesterolemia (FH); reduced LDL uptake was observed in assays performed on patient fibroblasts as well as in in vitro assays (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6; Maurer F et al. Swiss Med Wkly, 2016 Aug;146:w14326; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). Based on internal structural analysis, this variant is expected to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Nov 10, 2024