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NM_000527.5(LDLR):c.1529C>T (p.Thr510Met) AND Hypercholesterolemia, familial, 1

Germline classification:
Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:
Jun 15, 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:
RCV000237591.11

Allele description [Variation Report for NM_000527.5(LDLR):c.1529C>T (p.Thr510Met)]

NM_000527.5(LDLR):c.1529C>T (p.Thr510Met)

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.1529C>T (p.Thr510Met)
HGVS:
  • NC_000019.10:g.11113705C>T
  • NG_009060.1:g.29325C>T
  • NM_000527.5:c.1529C>TMANE SELECT
  • NM_001195798.2:c.1529C>T
  • NM_001195799.2:c.1406C>T
  • NM_001195800.2:c.1025C>T
  • NM_001195803.2:c.1148C>T
  • NP_000518.1:p.Thr510Met
  • NP_000518.1:p.Thr510Met
  • NP_001182727.1:p.Thr510Met
  • NP_001182728.1:p.Thr469Met
  • NP_001182729.1:p.Thr342Met
  • NP_001182732.1:p.Thr383Met
  • LRG_274t1:c.1529C>T
  • LRG_274:g.29325C>T
  • NC_000019.9:g.11224381C>T
  • NM_000527.4(LDLR):c.1529C>T
  • NM_000527.4:c.1529C>T
  • c.1529C>T
Protein change:
T342M
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000900; dbSNP: rs755154048
NCBI 1000 Genomes Browser:
rs755154048
Molecular consequence:
  • NM_000527.5:c.1529C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1529C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1406C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1025C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1148C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000295484LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)
Likely pathogenic
(Mar 25, 2016)
germlineliterature only

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

Citation Link,

SCV000540811Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Nov 5, 2016)
unknownclinical testing

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

SCV001422918Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 22, 2020)
germlinecuration

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001440425Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Dec 6, 2022)
unknownclinical testing

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

SCV004822470All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Jun 15, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes3not providednot provided3not providedliterature only
not providedgermlineunknown1not providednot provided108544not providedclinical testing, curation
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
Caucasianunknownyes11not provided3964not providedclinical testing

Citations

PubMed

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]
PMID:
15199436

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]
PMID:
16542394
See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295484.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (3)
2not provided1not providednot providedliterature only PubMed (3)
3not provided1not providednot providedliterature only PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540811.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian1not providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyes3964Whole bloodnot provided1not provided1not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422918.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

The p.Thr510Met variant in LDLR has been reported in 8 individuals (5 Norwegian, 2 Danish, 1 Czech) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 1 family (PMID: 15199436, 22698793, 16542394), and has been identified in 0.005782% (2/34592) of Latino chromosomes and 0.0008793% (1/113732) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755154048). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 251886). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP1_Moderate, PP3, PS4_Supporting (Richards 2015).

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440425.2

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

Description

_x000D_In the same patient the variant NM_000527.5:c.798T>A was identified. Criteria applied: PS4_MOD, PP1_MOD, PM2_SUP, PP3

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

From All of Us Research Program, National Institutes of Health, SCV004822470.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

This missense variant (also known as p.Thr489Met in the mature protein) is located in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 16542394, 22698793). This variant has also been identified in 4/246252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 provided1not providednot providednot provided

Last Updated: Sep 29, 2024