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:: RCV000237591.10

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:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295484	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 16542394, 15199436, 22698793 Citation Link,
SCV000540811	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation See additional submitters Centre of Molecular Biology and Gene Therapy, University Hospital Brno	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 5, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 22698793
SCV001422918	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 15199436, 16542394, 22698793, 25741868 Citation Link,
SCV001440425	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 6, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004822470	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16542394, 22698793, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	3	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, curation
Caucasian	unknown	yes	1	1	not provided	3964	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (3)
2	not provided	1	not provided	not provided	literature only	PubMed (3)
3	not provided	1	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	3964	Whole blood	not provided		1	not provided	1	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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