NM_000527.5(LDLR):c.1837G>A (p.Val613Ile) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Mar 28, 2025
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000210230.26

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:: 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
SCV000266314	Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT	criteria provided, single submitter (Mayo Cardiovascular Biomarkers Research Laboratory LDLR variant interpretation criteria, 2015)	Likely benign (Aug 31, 2015)	germline	research	PubMed (1) [See all records that cite this PMID] Kullo Lab Assertion Criteria_01072016.pdf, Citation Link,
SCV000295691	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16250003, 19837725 Citation Link,
SCV000588610	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000606532	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001653367	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003816523	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006304734	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain Significance (Mar 28, 2025)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	2	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research, curation
White	germline	no	not provided	not provided	not provided	1013	not provided	research

Citations

PubMed

Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals.

Safarova MS, Klee EW, Baudhuin LM, Winkler EM, Kluge ML, Bielinski SJ, Olson JE, Kullo IJ.

Eur J Hum Genet. 2017 Apr;25(4):410-415. doi: 10.1038/ejhg.2016.193. Epub 2017 Feb 1.

PubMed [citation]

PMID:: 28145427
PMCID:: PMC5386413

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 Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT, SCV000266314.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	not provided	not provided	not provided	research	PubMed (1)

Description

MAF =<0.3%

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	1013	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000295691.2

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

#	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

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588610.1

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

Description

%MAF(ExAC):0.001648

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606532.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Genome-Nilou Lab, SCV001653367.2

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003816523.3

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV006304734.1

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

Description

The NM_000527.5(LDLR):c.1837G>A (p.Val613Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00005340 (0.005%) in African/African American exomes+genomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases meeting FH criteria (1 case in PMID 19837725 (Whittall et al., 2010), UK; 1 case in PMID 16250003 (Fouchier et al., 2005), Netherlands).

#	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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