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

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 31, 2021
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:: RCV001177034.8

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)

Other names:

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

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]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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PREDICTED: Homo sapiens phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic...
PREDICTED: Homo sapiens phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD), transcript variant X29, mRNA
gi|2462510133|ref|XM_054337059.1|

Nucleotide
breast cancer type 1 susceptibility protein isoform 33 [Homo sapiens]
breast cancer type 1 susceptibility protein isoform 33 [Homo sapiens]
gi|2249629769|ref|NP_001394616.1|

Protein
Homologene neighbors for GEO Profiles (Select 119187452) (0)
GEO Profiles
Profile neighbors for GEO Profiles (Select 119190601) (199)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 119190601) (20)
GEO Profiles

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001341144	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 2, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001379760	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 31, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15199436, 16542394, 22698793, 28492532
SCV002086429	Natera, Inc.	no assertion criteria provided	Uncertain significance (Oct 29, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001341144

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 2, 2019)

germline

clinical testing

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

SCV001379760

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 31, 2021)

germline

clinical testing

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

SCV002086429

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Oct 29, 2020)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

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

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001341144.2

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

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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001379760.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces threonine with methionine at codon 510 of the LDLR protein (p.Thr510Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs755154048, ExAC 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15199436, 16542394, 22698793). This variant is also known as T489M. ClinVar contains an entry for this variant (Variation ID: 251886). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002086429.1

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

#	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

Last Updated: Oct 26, 2024

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