NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn) AND Familial hypercholesterolemia

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 27, 2023
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:: RCV000590648.11

Allele description

NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn)

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.1951G>A (p.Asp651Asn)

Other names:

NM_000527.5(LDLR):c.1951G>A

HGVS:

NC_000019.10:g.11120197G>A
NG_009060.1:g.35817G>A
NM_000527.5:c.1951G>AMANE SELECT
NM_001195798.2:c.1951G>A
NM_001195799.2:c.1828G>A
NM_001195800.2:c.1447G>A
NM_001195803.2:c.1570G>A
NP_000518.1:p.Asp651Asn
NP_000518.1:p.Asp651Asn
NP_001182727.1:p.Asp651Asn
NP_001182728.1:p.Asp610Asn
NP_001182729.1:p.Asp483Asn
NP_001182732.1:p.Asp524Asn
LRG_274t1:c.1951G>A
LRG_274:g.35817G>A
LRG_274p1:p.Asp651Asn
NC_000019.9:g.11230873G>A
NM_000527.4:c.1951G>A
c.1951G>A

Protein change:

D483N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000851; dbSNP: rs730882110

NCBI 1000 Genomes Browser:

rs730882110

Molecular consequence:

NM_000527.5:c.1951G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1951G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1828G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1447G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1570G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

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
SCV000697217	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 19, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17673191, 15890894, 15241806, 16627557 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001221619	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15241806, 25487149, 29396260, 30312929, 25647241, 16389549, 19318025, 28492532
SCV001352604	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 503436, 540849, 1221619, 2318907, 15241806, 15890894, 25487149, 25647241, 29396260, 30312929, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000697217

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(May 19, 2016)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001221619

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001352604

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 28, 2023)

germline

clinical testing

PubMed (11)
[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

Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation.

Verdeguer F, Castro C, Kubicek M, Pla D, Vila-Caballer M, Vinué A, Civeira F, Pocoví M, Calvete JJ, Andrés V.

Cardiovasc Res. 2007 Nov 1;76(2):340-50. Epub 2007 Jul 4.

PubMed [citation]

PMID:: 17673191

Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations?

Blesa S, Garcia-Garcia AB, Martinez-Hervas S, Mansego ML, Gonzalez-Albert V, Ascaso JF, Carmena R, Real JT, Chaves FJ.

Clin Chem. 2006 Jun;52(6):1021-5. Epub 2006 Apr 20.

PubMed [citation]

PMID:: 16627557

See all PubMed Citations (16)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697217.1

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

Description

Variant summary: The LDLR c.1951G>A (p.Asp651Asn) variant involves the alteration of a conserved nucleotide and is located in 'precursor homology' domain. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 1/131578 control chromosomes at a frequency of 0.0000076, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in three apparently non-related FH patients (Mozas_2004) as well as in one patient with myocardial infarction (Do_2015). Other missense changes at this codon such as Asp651Tyr has also been detected in FH patients, suggesting that the codon may be a mutational hot-spot. Taken together, it variant has been classified as a Probable Disease Variant (or likely pathogenic).

#	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 Invitae, SCV001221619.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 651 of the LDLR protein (p.Asp651Asn). This variant is present in population databases (rs730882110, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive LDLR-related conditions (PMID: 15241806, 25487149, 29396260, 30312929; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.D630N. ClinVar contains an entry for this variant (Variation ID: 183128). 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 expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). This variant disrupts the p.Asp651 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16389549, 19318025), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001352604.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This missense variant (also known as p.Asp630Asn in the mature protein) replaces aspartic acid with asparagine at codon 651 in the LDLR type B repeat 6 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A high-throughput functional study has shown that this variant may not cause a significant impact to LDL uptake (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 15241806, 15890894, 30312929; ClinVar SCV000540849.1, SCV002318907.1, SCV000503436.1, SCV001221619.4; Color internal data). It has also been reported in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has also been observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (PMID: 29396260), indicating that this variant contributes to disease. This variant has been identified in 1/251464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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: Sep 1, 2024

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