NM_000527.5(LDLR):c.534T>G (p.Asp178Glu) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 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:: RCV001201350.8

Allele description [Variation Report for NM_000527.5(LDLR):c.534T>G (p.Asp178Glu)]

NM_000527.5(LDLR):c.534T>G (p.Asp178Glu)

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.534T>G (p.Asp178Glu)

HGVS:

NC_000019.10:g.11105440T>G
NG_009060.1:g.21060T>G
NM_000527.5:c.534T>GMANE SELECT
NM_001195798.2:c.534T>G
NM_001195799.2:c.411T>G
NM_001195800.2:c.314-1952T>G
NM_001195803.2:c.314-1125T>G
NP_000518.1:p.Asp178Glu
NP_000518.1:p.Asp178Glu
NP_001182727.1:p.Asp178Glu
NP_001182728.1:p.Asp137Glu
LRG_274t1:c.534T>G
LRG_274:g.21060T>G
LRG_274p1:p.Asp178Glu
NC_000019.9:g.11216116T>G
NM_000527.4:c.534T>G
c.534T>G

Protein change:

D137E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000466; dbSNP: rs879254566

NCBI 1000 Genomes Browser:

rs879254566

Molecular consequence:

NM_001195800.2:c.314-1952T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1125T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.534T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.534T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.411T>G - 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
SCV000835802	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11196104, 12436241, 16389549, 28492532
SCV004358483	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 2600087, 3417658, 11196104, 17347910, 33418990, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000835802

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

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

SCV004358483

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 3, 2022)

germline

clinical testing

PubMed (6)
[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

Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.

Amsellem S, Briffaut D, Carrié A, Rabès JP, Girardet JP, Fredenrich A, Moulin P, Krempf M, Reznik Y, Vialettes B, de Gennes JL, Brukert E, Benlian P.

Hum Genet. 2002 Dec;111(6):501-10. Epub 2002 Sep 13.

PubMed [citation]

PMID:: 12436241

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.

Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, Wierzbicki AS.

J Mol Med (Berl). 2006 Mar;84(3):203-14. Epub 2005 Dec 31.

PubMed [citation]

PMID:: 16389549

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000835802.6

#	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 aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 178 of the LDLR protein (p.Asp178Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11196104; Invitae). This variant is also known as p.Asp157Glu. ClinVar contains an entry for this variant (Variation ID: 251287). 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.Asp178 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12436241, 16389549), 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, SCV004358483.1

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

Description

This missense variant (also known as p.Asp157Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 178 of the LDLR protein. This variant is located in the ligand binding domain in a region critical for LDL binding (PMID: 2600087, 3417658). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 11196104, 17347910, 33418990; Shakhtshneider et al, 2019, DOI: 10.1016/j.atherosclerosis.2019.06.883). This variant has not been identified 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 29, 2024

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