NM_000527.5(LDLR):c.2575G>A (p.Val859Met) AND Familial hypercholesterolemia

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000771548.11

Allele description [Variation Report for NM_000527.5(LDLR):c.2575G>A (p.Val859Met)]

NM_000527.5(LDLR):c.2575G>A (p.Val859Met)

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.2575G>A (p.Val859Met)

Other names:

NM_000527.5(LDLR):c.2575G>A; p.Val859Met

HGVS:

NC_000019.10:g.11131308G>A
NG_009060.1:g.46928G>A
NM_000527.5:c.2575G>AMANE SELECT
NM_001195798.2:c.2569G>A
NM_001195799.2:c.2452G>A
NM_001195800.2:c.2071G>A
NM_001195803.2:c.2041G>A
NP_000518.1:p.Val859Met
NP_000518.1:p.Val859Met
NP_001182727.1:p.Val857Met
NP_001182728.1:p.Val818Met
NP_001182729.1:p.Val691Met
NP_001182732.1:p.Val681Met
LRG_274t1:c.2575G>A
LRG_274:g.46928G>A
LRG_274p1:p.Val859Met
NC_000019.9:g.11241984G>A
NM_000527.4:c.2575G>A
c.2575G>A

Protein change:

V681M

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001670; dbSNP: rs202049029

NCBI 1000 Genomes Browser:

rs202049029

Molecular consequence:

NM_000527.5:c.2575G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2569G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2452G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.2071G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.2041G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000904110	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Feb 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002086889	Natera, Inc.	no assertion criteria provided	Likely benign (Jun 4, 2021)	germline	clinical testing
SCV003301335	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23021490, 25487149, 25386756, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000904110

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Feb 21, 2023)

germline

clinical testing

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

SCV002086889

Natera, Inc.

no assertion criteria provided

Likely benign
(Jun 4, 2021)

germline

clinical testing

SCV003301335

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 11, 2024)

germline

clinical testing

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

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

In vitro functional characterization of missense mutations in the LDLR gene.

Silva S, Alves AC, Patel D, Malhó R, Soutar AK, Bourbon M.

Atherosclerosis. 2012 Nov;225(1):128-34. doi: 10.1016/j.atherosclerosis.2012.08.017. Epub 2012 Aug 20.

PubMed [citation]

PMID:: 23021490

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000904110.3

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

#	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., SCV002086889.1

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003301335.2

#	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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 859 of the LDLR protein (p.Val859Met). This variant is present in population databases (rs202049029, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 23021490, 25487149). ClinVar contains an entry for this variant (Variation ID: 252360). 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 not expected to disrupt LDLR protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25386756). 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

Last Updated: May 16, 2025

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