NM_000527.5(LDLR):c.1721G>A (p.Arg574His) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (7 submissions)
Last evaluated:: Feb 13, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000237135.15

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]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295612	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 22881376, 23375686 Citation Link,
SCV000588604	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000607631	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002506356	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Feb 13, 2022)	germline	curation	Citation Link,
SCV004014673	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (Feb 2, 2023)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 35753512, 23375686, 33994402, 33740630, 35339733, 34037665, 20018285 Citation Link,
SCV004045974	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Sep 4, 2023)	germline	clinical testing	Citation Link,
SCV004800912	Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	no assertion criteria provided	Likely pathogenic	germline	research

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	2	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment.

Usifo E, Leigh SE, Whittall RA, Lench N, Taylor A, Yeats C, Orengo CA, Martin AC, Celli J, Humphries SE.

Ann Hum Genet. 2012 Sep;76(5):387-401. doi: 10.1111/j.1469-1809.2012.00724.x.

PubMed [citation]

PMID:: 22881376

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

See all PubMed Citations (9)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295612.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	PubMed (2)

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

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588604.1

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

Description

%MAF(ExAC):0.0008237

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607631.1

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

Description

%MAF(ExAC):0.0008237

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506356.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

NM_000527.5(LDLR):c.1721G>A (p.Arg574His) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_strong - PMID: 20018285 - 6 informative meioses in 1 family. PM2 - PopMax MAF = 0.0001129 (0.01129%) in Latino exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.971. PP4 - Variant meets PM2. PMID: 20018285 - 1 case with DLCN > 6.

#	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 Illumina Laboratory Services, Illumina, SCV004014673.1

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

Description

The LDLR c.1721G>A (p.Arg574His) missense variant results in the substitution of arginine at amino acid position 574 with histidine. This variant has been reported in a heterozygous state in at least six probands with hypercholesterolemia (PMID: 20018285; PMID: 35753512; PMID: 23375686; PMID: 33994402; PMID:33740630; PMID: 35339733; PMID: 34037665). The c.1712G>A was reported in a heterozygous state in a 60-year-old female with angina pectoris and pseudoxanthoma elasticum associated with elevated plasma LDL cholesterol levels, who also carried two ABCC6 variants in a compound heterozygous state. The c.1721G>A variant segregated with elevated LDL cholesterol levels in six additional family members (PMID: 20018285). This variant is reported in the Genome Aggregation Database in four alleles at a frequency of 0.000113 in the Latino/Admixed American population (version 2.1.1). Based on the available evidence, the c.1721G>A (p.Arg574His) variant is classified as likely pathogenic for familial hypercholesterolemia.

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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV004045974.1

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

#	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		1	not provided	not provided	not provided

From Medical Laboratory Center, Huzhou Maternal and Child Health Hospital, SCV004800912.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	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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