NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jan 29, 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:: RCV000791360.23

Allele description [Variation Report for NM_000527.5(LDLR):c.798T>A (p.Asp266Glu)]

NM_000527.5(LDLR):c.798T>A (p.Asp266Glu)

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.798T>A (p.Asp266Glu)

Other names:

NP_000518.1:p.D266E; NM_000527.5(LDLR):c.798T>A

HGVS:

NC_000019.10:g.11106668T>A
NG_009060.1:g.22288T>A
NM_000527.5:c.798T>AMANE SELECT
NM_001195798.2:c.798T>A
NM_001195799.2:c.675T>A
NM_001195800.2:c.314-724T>A
NM_001195803.2:c.417T>A
NP_000518.1:p.Asp266Glu
NP_000518.1:p.Asp266Glu
NP_001182727.1:p.Asp266Glu
NP_001182728.1:p.Asp225Glu
NP_001182732.1:p.Asp139Glu
LRG_274t1:c.798T>A
LRG_274:g.22288T>A
LRG_274p1:p.Asp266Glu
NC_000019.9:g.11217344T>A
NM_000527.2:c.798T>A
NM_000527.4:c.798T>A
P01130:p.Asp266Glu
c.798T>A

Protein change:

D139E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000117; UniProtKB: P01130#VAR_005347; dbSNP: rs139043155

NCBI 1000 Genomes Browser:

rs139043155

Molecular consequence:

NM_001195800.2:c.314-724T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.798T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.798T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.675T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.417T>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence - Comment(s)

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV000544696	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1301956, 20663204, 21310417, 22698793, 23375686, 26238499, 11196104, 28492532
SCV001355074	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 1301956, 20663204, 21310417, 22698793, 23375686, 26238499, 27596133, 31345425, 33269076, 33418990, 33740630, 34037665, 35741760, 25741868
SCV001442758	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 8, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1301956, 21310417, 23375686, 22698793, 20663204, 30795984 Citation Link,
SCV001482460	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	research	PubMed (2) [See all records that cite these PMIDs] 29261184, 25741868
SCV002086388	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 5, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia.

Weiss N, Binder G, Keller C.

J Inherit Metab Dis. 2000 Dec;23(8):778-90.

PubMed [citation]

PMID:: 11196104

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (18)

Details of each submission

From Invitae, SCV000544696.10

#	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 glutamic acid, which is acidic and polar, at codon 266 of the LDLR protein (p.Asp266Glu). This variant is present in population databases (rs139043155, gnomAD 0.008%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499). This variant is also known as p.Asp245Glu. ClinVar contains an entry for this variant (Variation ID: 161287). 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%. This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11196104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV001355074.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This missense variant (also known as p.Asp245Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 266 in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a homozygous carrier has shown that this variant causes a significant decrease of LDLR (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia and is known to be a common cause of disease in the Czech, German and Austrian populations (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499, 27596133, 31345425, 33269076, 33418990, 33740630, 34037665, 35741760). This variant has been identified in 10/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp266Asn, p.Asp266Gly, and p.Asp266Val) are considered to be disease-causing (ClinVar variation ID: 226334, 251457, and 251458), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442758.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: LDLR c.798T>A (p.Asp266Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes. c.798T>A has been widely reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Tichy_2012, Goldmann_2010, Duskova_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hobbs_1992). The most pronounced variant effect results in 15%-30% of normal LDL receptor activity. Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic/pathogenic, n=16). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was 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 Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine, SCV001482460.1

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

From Natera, Inc., SCV002086388.1

#	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: Apr 20, 2024

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