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NM_000527.5(LDLR):c.859G>A (p.Gly287Ser) AND Familial hypercholesterolemia

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Oct 22, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV001176040.15

Allele description [Variation Report for NM_000527.5(LDLR):c.859G>A (p.Gly287Ser)]

NM_000527.5(LDLR):c.859G>A (p.Gly287Ser)

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.859G>A (p.Gly287Ser)
Other names:
NM_000527.5(LDLR):c.859G>A; p.Gly287Ser
HGVS:
  • NC_000019.10:g.11107433G>A
  • NG_009060.1:g.23053G>A
  • NM_000527.5:c.859G>AMANE SELECT
  • NM_001195798.2:c.859G>A
  • NM_001195799.2:c.736G>A
  • NM_001195800.2:c.355G>A
  • NM_001195803.2:c.478G>A
  • NP_000518.1:p.Gly287Ser
  • NP_000518.1:p.Gly287Ser
  • NP_001182727.1:p.Gly287Ser
  • NP_001182728.1:p.Gly246Ser
  • NP_001182729.1:p.Gly119Ser
  • NP_001182732.1:p.Gly160Ser
  • LRG_274t1:c.859G>A
  • LRG_274:g.23053G>A
  • LRG_274p1:p.Gly287Ser
  • NC_000019.9:g.11218109G>A
  • NM_000527.4:c.859G>A
  • c.859G>A
Protein change:
G119S
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001848; dbSNP: rs375495026
NCBI 1000 Genomes Browser:
rs375495026
Molecular consequence:
  • NM_000527.5:c.859G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.859G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.736G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.355G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.478G>A - 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
SCV001339857Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 1, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003260467Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Oct 22, 2023) 		germlineclinical testing

PubMed (5)
[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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic.

Futema M, Whittall RA, Kiley A, Steel LK, Cooper JA, Badmus E, Leigh SE, Karpe F, Neil HA; Simon Broome Register Group., Humphries SE.

Atherosclerosis. 2013 Jul;229(1):161-8. doi: 10.1016/j.atherosclerosis.2013.04.011. Epub 2013 Apr 18.

PubMed [citation]
PMID:
23669246
PMCID:
PMC3701838
See all PubMed Citations (6)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001339857.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This missense variant (also known as p.Gly266Ser in the mature protein) replaces glycine with serine at codon 287 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 23669246). This variant has been identified in 3/282818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003260467.2

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the LDLR protein (p.Gly287Ser). This variant is present in population databases (rs375495026, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 23669246, 33740630). ClinVar contains an entry for this variant (Variation ID: 161280). 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 with a positive predictive value of 95%. This variant disrupts the p.Gly287 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12730724, 17196209; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 26, 2024