NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 12, 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:: RCV001523922.5

Allele description [Variation Report for NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp)]

NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp)

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.2531G>A (p.Gly844Asp)

Other names:

G823D; FH Turku; FH Finn-1; NM_000527.5(LDLR):c.2531G>A

HGVS:

NC_000019.10:g.11129654G>A
NG_009060.1:g.45274G>A
NM_000527.5:c.2531G>AMANE SELECT
NM_001195798.2:c.2531G>A
NM_001195799.2:c.2408G>A
NM_001195800.2:c.2027G>A
NM_001195803.2:c.1997G>A
NP_000518.1:p.Gly844Asp
NP_001182727.1:p.Gly844Asp
NP_001182728.1:p.Gly803Asp
NP_001182729.1:p.Gly676Asp
NP_001182732.1:p.Gly666Asp
LRG_274t1:c.2531G>A
LRG_274:g.45274G>A
NC_000019.9:g.11240330G>A
NM_000527.4:c.2531G>A
P01130:p.Gly844Asp
c.2531G>A

Protein change:

G666D; GLY823ASP

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001663; UniProtKB: P01130#VAR_005420; OMIM: 606945.0052; dbSNP: rs121908037

NCBI 1000 Genomes Browser:

rs121908037

Molecular consequence:

NM_000527.5:c.2531G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2531G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2408G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.2027G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1997G>A - 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
SCV001733662	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 11, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004297888	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 12, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11389828, 7573037, 32522009, 33955087, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001733662

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 11, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004297888

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 12, 2023)

germline

clinical testing

PubMed (5)
[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

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

A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor.

Koivisto UM, Hubbard AL, Mellman I.

Cell. 2001 Jun 1;105(5):575-85.

PubMed [citation]

PMID:: 11389828

See all PubMed Citations (6)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001733662.1

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

Description

This missense variant (also known as p.Gly823Asp in the mature protein and as FH-Turku) replaces glycine with aspartic acid at codon 844 in the cytoplasmic domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the variant interferes with the basolateral sorting of LDLR with the effect that the protein was mis-targeted to the apical surface of the cell (PMID: 11389828). As a result, binding, internalization and degradation of LDL particles is significantly reduced (PMID: 7573037). Expression of the mutant protein failed to correct hypercholesterolemia in LDLR-deficient mice (PMID: 11389828). This variant has been reported in over ten unrelated individuals affected with familial hypercholesterolemia (PMID: 7573037). 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 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004297888.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 11389828). 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. ClinVar contains an entry for this variant (Variation ID: 3734). This variant is also known as p.Gly823Asp, FH-Turku. This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 7573037, 32522009, 33955087). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 844 of the LDLR protein (p.Gly844Asp).

#	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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