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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 9, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002411086.3

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:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002716015	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 9, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20018285, 23375686, 24529145, 25461735, 33994402, 34314377, 35339733 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002716015

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 9, 2024)

germline

clinical testing

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

Citation Link

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

Pseudoxanthoma elasticum and familial hypercholesterolemia: a deleterious combination of cardiovascular risk factors.

Pisciotta L, Tarugi P, Borrini C, Bellocchio A, Fresa R, Guerra D, Quaglino D, Ronchetti I, Calandra S, Bertolini S.

Atherosclerosis. 2010 May;210(1):173-6. doi: 10.1016/j.atherosclerosis.2009.11.028. Epub 2009 Nov 24.

PubMed [citation]

PMID:: 20018285

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002716015.2

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

Description

The c.1721G>A (p.R574H) alteration is located in exon 12 (coding exon 12) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1721, causing the arginine (R) at amino acid position 574 to be replaced by a histidine (H). This alteration has been detected in several unrelated probands reported to have familial hypercholesterolemia (FH), and has shown segregation with hypercholesterolemia in at least one family (Pisciotta, 2010; Bertolini, 2013; Jannes, 2015; Huang, 2022; Noto, 2022; external communication; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration 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: Oct 20, 2024

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