NM_000527.5(LDLR):c.1837G>A (p.Val613Ile) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 29, 2024
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:: RCV000771315.19

Allele description [Variation Report for NM_000527.5(LDLR):c.1837G>A (p.Val613Ile)]

NM_000527.5(LDLR):c.1837G>A (p.Val613Ile)

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.1837G>A (p.Val613Ile)

Other names:

NM_000527.5(LDLR):c.1837G>A

HGVS:

NC_000019.10:g.11116990G>A
NG_009060.1:g.32610G>A
NM_000527.5:c.1837G>AMANE SELECT
NM_001195798.2:c.1837G>A
NM_001195799.2:c.1714G>A
NM_001195800.2:c.1333G>A
NM_001195803.2:c.1456G>A
NP_000518.1:p.Val613Ile
NP_000518.1:p.Val613Ile
NP_001182727.1:p.Val613Ile
NP_001182728.1:p.Val572Ile
NP_001182729.1:p.Val445Ile
NP_001182732.1:p.Val486Ile
LRG_274t1:c.1837G>A
LRG_274:g.32610G>A
LRG_274p1:p.Val613Ile
NC_000019.9:g.11227666G>A
NM_000527.4:c.1837G>A
c.1837G>A

Protein change:

V445I

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000250; dbSNP: rs148181903

NCBI 1000 Genomes Browser:

rs148181903

Molecular consequence:

NM_000527.5:c.1837G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1837G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1714G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1333G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1456G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Synonyms:: Familial hypercholesterolaemia
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
SCV000903571	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16250003, 19837725, 25741868
SCV000945773	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 20, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16250003, 19837725, 28492532
SCV002086854	Natera, Inc.	no assertion criteria provided	Uncertain significance (Feb 6, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000903571

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 29, 2024)

germline

clinical testing

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

SCV000945773

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 20, 2022)

germline

clinical testing

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

SCV002086854

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Feb 6, 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

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000903571.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces valine with isoleucine at codon 613 of the LDLR protein. This variant is also known as p.Val592Ile in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 19837725). This variant has been identified in 7/251438 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.

#	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, SCV000945773.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 613 of the LDLR protein (p.Val613Ile). This variant is present in population databases (rs148181903, gnomAD 0.007%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 16250003, 19837725). ClinVar contains an entry for this variant (Variation ID: 161288). 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. 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., SCV002086854.1

#	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: Dec 7, 2025

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