NM_000527.5(LDLR):c.1721G>A (p.Arg574His) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 1, 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:: RCV000791382.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1721G>A (p.Arg574His)]

NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

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.1721G>A (p.Arg574His)

Other names:

NM_000527.5(LDLR):c.1721G>A

HGVS:

NC_000019.10:g.11116874G>A
NG_009060.1:g.32494G>A
NM_000527.5:c.1721G>AMANE SELECT
NM_001195798.2:c.1721G>A
NM_001195799.2:c.1598G>A
NM_001195800.2:c.1217G>A
NM_001195803.2:c.1340G>A
NP_000518.1:p.Arg574His
NP_000518.1:p.Arg574His
NP_001182727.1:p.Arg574His
NP_001182728.1:p.Arg533His
NP_001182729.1:p.Arg406His
NP_001182732.1:p.Arg447His
LRG_274t1:c.1721G>A
LRG_274:g.32494G>A
LRG_274p1:p.Arg574His
NC_000019.9:g.11227550G>A
NM_000527.4:c.1721G>A
P01130:p.Arg574His
c.1721G>A

Protein change:

R406H

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000233; UniProtKB: P01130#VAR_072852

Molecular consequence:

NM_000527.5:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1340G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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HPODL_03743 [Ogataea parapolymorpha DL-1]
HPODL_03743 [Ogataea parapolymorpha DL-1]
Gene ID:25773177

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000836468	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23375686, 11462246, 19446849, 20018285, 25461735, 26892515, 28492532
SCV001355014	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 20018285, 23375686, 25064003, 25461735, 33740630, 33994402, 34037665, 34314377, 34573395, 35753512, 25741868
SCV002522197	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000836468

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 1, 2023)

germline

clinical testing

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

SCV001355014

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 10, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002522197

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 6, 2021)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]

PMID:: 11462246

The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia.

Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, Bertolini S.

J Pediatr. 2009 Aug;155(2):199-204.e2. doi: 10.1016/j.jpeds.2009.02.022. Epub 2009 May 15.

PubMed [citation]

PMID:: 19446849

See all PubMed Citations (15)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000836468.7

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 574 of the LDLR protein (p.Arg574His). This variant is present in population databases (rs777188764, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20018285, 23375686, 25461735; Invitae). ClinVar contains an entry for this variant (Variation ID: 251996). 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.Arg574 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11462246, 19446849, 20018285, 25461735, 26892515; Invitae). 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, SCV001355014.3

#	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 replaces arginine with histidine at codon 574 of the LDLR protein. This variant is also known as p.Arg553His in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the EGF precursor homology domain of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least eight individuals affected with familial hypercholesterolemia (PMID: 20018285, 23375686, 25064003, 25461735, 33740630, 33994402, 34037665, 34314377, 34573395, 35753512; Color internal data). This variant has been identified in 9/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant, p.Arg574Cys, is considered to be disease-causing (ClinVar variation ID: 183123), suggesting that arginine at this codon position is important for LDLR 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 National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health, SCV002522197.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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