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NM_000527.5(LDLR):c.323C>T (p.Thr108Met) AND Hypercholesterolemia, familial, 1

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Dec 1, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000237396.3

Allele description [Variation Report for NM_000527.5(LDLR):c.323C>T (p.Thr108Met)]

NM_000527.5(LDLR):c.323C>T (p.Thr108Met)

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.323C>T (p.Thr108Met)
HGVS:
  • NC_000019.10:g.11105229C>T
  • NG_009060.1:g.20849C>T
  • NM_000527.5:c.323C>TMANE SELECT
  • NM_001195798.2:c.323C>T
  • NM_001195799.2:c.200C>T
  • NM_001195800.2:c.314-2163C>T
  • NM_001195803.2:c.314-1336C>T
  • NP_000518.1:p.Thr108Met
  • NP_001182727.1:p.Thr108Met
  • NP_001182728.1:p.Thr67Met
  • LRG_274:g.20849C>T
  • NC_000019.9:g.11215905C>T
  • c.323C>T
Protein change:
T108M
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000767; dbSNP: rs750126678
NCBI 1000 Genomes Browser:
rs750126678
Molecular consequence:
  • NM_001195800.2:c.314-2163C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1336C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.323C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.323C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.200C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Hypercholesterolemia, familial, 1
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000294627LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Uncertain significance
(Mar 25, 2016) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004834887All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 1, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedliterature only
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

Eight novel LDL receptor gene mutations among patients under LDL apheresis in Dresden and Leipzig.

Bochmann H, Geisel J, Herrmann W, Purcz T, Reuter W, Julius U, Metzler W, Bergmann S, Jaross W, Gehrisch S.

Hum Mutat. 2001;17(1):76-7.

PubMed [citation]
PMID:
11139254

A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia.

Di Taranto MD, Giacobbe C, Buonaiuto A, Calcaterra I, Palma D, Maione G, Iannuzzo G, Di Minno MND, Rubba P, Fortunato G.

J Clin Med. 2020 Jan 14;9(1). doi:pii: E219. 10.3390/jcm9010219.

PubMed [citation]
PMID:
31947532
PMCID:
PMC7019873
See all PubMed Citations (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294627.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004834887.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (3)

Description

This missense variant replaces threonine with methionine at codon 108 of the LDLR protein. This variant is also known as p.Thr87Met in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11139254, 31947532). This variant has been identified in 1/250164 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
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: May 7, 2024