NM_000527.5(LDLR):c.1774G>A (p.Gly592Arg) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 17, 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:: RCV001178326.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1774G>A (p.Gly592Arg)]

NM_000527.5(LDLR):c.1774G>A (p.Gly592Arg)

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.1774G>A (p.Gly592Arg)

Other names:

NM_000527.4(LDLR):c.1774G>A

HGVS:

NC_000019.10:g.11116927G>A
NG_009060.1:g.32547G>A
NM_000527.5:c.1774G>AMANE SELECT
NM_001195798.2:c.1774G>A
NM_001195799.2:c.1651G>A
NM_001195800.2:c.1270G>A
NM_001195803.2:c.1393G>A
NP_000518.1:p.Gly592Arg
NP_000518.1:p.Gly592Arg
NP_001182727.1:p.Gly592Arg
NP_001182728.1:p.Gly551Arg
NP_001182729.1:p.Gly424Arg
NP_001182732.1:p.Gly465Arg
LRG_274t1:c.1774G>A
LRG_274:g.32547G>A
LRG_274p1:p.Gly592Arg
NC_000019.9:g.11227603G>A
NM_000527.4:c.1774G>A

Protein change:

G424R

Links:

dbSNP: rs763147599

NCBI 1000 Genomes Browser:

rs763147599

Molecular consequence:

NM_000527.5:c.1774G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1774G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1651G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1270G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1393G>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
SCV001342731	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 14, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 503411, 2568019, 27050191, 27932355, 33732287, 35910211, 25741868
SCV001399560	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 17, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 27932355, 33740630, 35910211, 15864114, 20663204, 21310417, 21925044, 23375686, 26238499, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001342731

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 14, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001399560

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 17, 2023)

germline

clinical testing

PubMed (10)
[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

Healthkeeping in the workplace.

Hickey P.

Occup Health Saf. 1979 Oct;48(7):61-3. No abstract available.

PubMed [citation]

PMID:: 503411

[Role of the adrenoreceptor apparatus in the mechanisms of bronchospasm and methods of diagnosing the types of adrenergic imbalance in patients with bronchial asthma].

Zonis BIa.

Ter Arkh. 1989;61(3):43-6. Russian. No abstract available.

PubMed [citation]

PMID:: 2568019

See all PubMed Citations (15)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001342731.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant (also known as p.Gly571Arg in the mature protein and as p.Gly465Arg based on a different transcript NM_001195803.2) replaces glycine with arginine at codon 592 in the fifth LDLR type B repeat 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in eight individuals affected with familial hypercholesterolemia including one homozygote with premature coronary artery disease (PMID: 27932355, 33732287, 35910211, ClinVar SCV000503411.1, SCV002568019.1). This variant has also been observed in two unaffected individuals (PMID: 27050191, 35910211). This variant has been identified in 4/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly592Glu, is known to cause disease (Clinvar variation ID:161271), indicating that glycine at this position is important for the protein function. 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001399560.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 592 of the LDLR protein (p.Gly592Arg). This variant is present in population databases (rs763147599, gnomAD 0.01%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 27932355, 33740630, 35910211). This variant is also known as c.1393G>A (p.Gly465Arg). ClinVar contains an entry for this variant (Variation ID: 373769). 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.Gly592 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15864114, 20663204, 21310417, 21925044, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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: Oct 13, 2024

ClinVar

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