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NM_000527.5(LDLR):c.901G>T (p.Asp301Tyr) AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 23, 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:
RCV002518481.3

Allele description [Variation Report for NM_000527.5(LDLR):c.901G>T (p.Asp301Tyr)]

NM_000527.5(LDLR):c.901G>T (p.Asp301Tyr)

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.901G>T (p.Asp301Tyr)
HGVS:
  • NC_000019.10:g.11107475G>T
  • NG_009060.1:g.23095G>T
  • NM_000527.5:c.901G>TMANE SELECT
  • NM_001195798.2:c.901G>T
  • NM_001195799.2:c.778G>T
  • NM_001195800.2:c.397G>T
  • NM_001195803.2:c.520G>T
  • NP_000518.1:p.Asp301Tyr
  • NP_001182727.1:p.Asp301Tyr
  • NP_001182728.1:p.Asp260Tyr
  • NP_001182729.1:p.Asp133Tyr
  • NP_001182732.1:p.Asp174Tyr
  • LRG_274:g.23095G>T
  • NC_000019.9:g.11218151G>T
  • c.901G>T
Protein change:
D133Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000511; dbSNP: rs879254713
NCBI 1000 Genomes Browser:
rs879254713
Molecular consequence:
  • NM_000527.5:c.901G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.901G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.778G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.397G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.520G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial hypercholesterolemia
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003442668Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Sep 23, 2022) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

A high incidence of mutations in exon 6 of the low-density lipoprotein receptor gene in Greek familial hypercholesterolemia patients, including a novel mutation.

Mavroidis N, Traeger-Synodinos J, Kanavakis E, Drogari E, Matsaniotis N, Humphries SE, Day IN, Kattamis C.

Hum Mutat. 1997;9(3):274-6. No abstract available.

PubMed [citation]
PMID:
9090532

Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.

Chaves FJ, Real JT, García-García AB, Civera M, Armengod ME, Ascaso JF, Carmena R.

J Clin Endocrinol Metab. 2001 Oct;86(10):4926-32.

PubMed [citation]
PMID:
11600564
See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442668.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp301 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9090532, 11600564, 15241806, 16250003, 25461735, 25463123). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251512). This variant is also known as D280Y. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12417285, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 301 of the LDLR protein (p.Asp301Tyr).

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

Last Updated: Sep 29, 2024