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NM_000527.5(LDLR):c.902A>G (p.Asp301Gly) AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 22, 2023
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:
RCV001233629.8

Allele description [Variation Report for NM_000527.5(LDLR):c.902A>G (p.Asp301Gly)]

NM_000527.5(LDLR):c.902A>G (p.Asp301Gly)

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.902A>G (p.Asp301Gly)
Other names:
FH Greece-3
HGVS:
  • NC_000019.10:g.11107476A>G
  • NG_009060.1:g.23096A>G
  • NM_000527.5:c.902A>GMANE SELECT
  • NM_001195798.2:c.902A>G
  • NM_001195799.2:c.779A>G
  • NM_001195800.2:c.398A>G
  • NM_001195803.2:c.521A>G
  • NP_000518.1:p.Asp301Gly
  • NP_000518.1:p.Asp301Gly
  • NP_001182727.1:p.Asp301Gly
  • NP_001182728.1:p.Asp260Gly
  • NP_001182729.1:p.Asp133Gly
  • NP_001182732.1:p.Asp174Gly
  • LRG_274t1:c.902A>G
  • LRG_274:g.23096A>G
  • LRG_274p1:p.Asp301Gly
  • NC_000019.9:g.11218152A>G
  • NM_000527.4:c.902A>G
  • P01130:p.Asp301Gly
  • c.902A>G
Protein change:
D133G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001860; UniProtKB: P01130#VAR_072840
Molecular consequence:
  • NM_000527.5:c.902A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.902A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.779A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.398A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.521A>G - 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
SCV001406233Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Apr 22, 2023) 		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

Activity-associated effect of LDL receptor missense variants located in the cysteine-rich repeats.

Etxebarria A, Benito-Vicente A, Stef M, Ostolaza H, Palacios L, Martin C.

Atherosclerosis. 2015 Feb;238(2):304-12. doi: 10.1016/j.atherosclerosis.2014.12.026. Epub 2014 Dec 20.

PubMed [citation]
PMID:
25545329

Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.

Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H.

Atherosclerosis. 2002 Dec;165(2):335-42. Erratum in: Atherosclerosis. 2004 Jun;174(2):399-400.

PubMed [citation]
PMID:
12417285
See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001406233.5

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

Description

Experimental studies have shown that this missense change affects LDLR function (PMID: 25545329). 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 observed in individuals with LDLR-related conditions (PMID: 12417285), which suggests that this may be a clinically significant amino acid residue. 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: 251514). This variant is also known as Asp280Gly (D280G). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 9090532, 11600564, 15241806, 16250003, 25461735, 25463123). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 301 of the LDLR protein (p.Asp301Gly).

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

Last Updated: Sep 29, 2024