NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro) AND Hypercholesterolemia, familial, 1

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Apr 28, 2023
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:: RCV000211597.13

Allele description

NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)

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.1049G>C (p.Arg350Pro)

Other names:

FH Alghero; NM_000527.5(LDLR):c.1049G>C

HGVS:

NC_000019.10:g.11110760G>C
NG_009060.1:g.26380G>C
NM_000527.5:c.1049G>CMANE SELECT
NM_001195798.2:c.1049G>C
NM_001195799.2:c.926G>C
NM_001195800.2:c.545G>C
NM_001195803.2:c.668G>C
NP_000518.1:p.Arg350Pro
NP_000518.1:p.Arg350Pro
NP_001182727.1:p.Arg350Pro
NP_001182728.1:p.Arg309Pro
NP_001182729.1:p.Arg182Pro
NP_001182732.1:p.Arg223Pro
LRG_274t1:c.1049G>C
LRG_274:g.26380G>C
LRG_274p1:p.Arg350Pro
NC_000019.9:g.11221436G>C
NM_000527.4:c.1049G>C
P01130:p.Arg350Pro
c.1049G>C

Protein change:

R182P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001337; UniProtKB: P01130#VAR_005368; dbSNP: rs875989914

NCBI 1000 Genomes Browser:

rs875989914

Molecular consequence:

NM_000527.5:c.1049G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1049G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.926G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.545G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.668G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000268596	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15100232, 9026534, 25741868
SCV000295162	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003831265	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004022403	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Apr 28, 2023)	germline	curation	Citation Link

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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, curation
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only

Citations

PubMed

Global defects in the expression and function of the low density lipoprotein receptor (LDLR) associated with two familial hypercholesterolemia mutations resulting in misfolding of the LDLR epidermal growth factor-AB pair.

Boswell EJ, Jeon H, Blacklow SC, Downing AK.

J Biol Chem. 2004 Jul 16;279(29):30611-21. Epub 2004 Apr 20.

PubMed [citation]

PMID:: 15100232

Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom.

Webb JC, Sun XM, McCarthy SN, Neuwirth C, Thompson GR, Knight BL, Soutar AK.

J Lipid Res. 1996 Feb;37(2):368-81.

PubMed [citation]

PMID:: 9026534

See all PubMed Citations (3)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268596.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

LDLR p.Arg350Pro (originally Arg329Pro, FH Alghero) missense variant has previously been identified in multiple cohorts of familial hypercholesterolemia patients. In vitro studies demonstrated that LDLR p.Arg350Pro affected protein folding and surface expression, resulting in decreased LDL-receptor activity (PMID: 15100232, 9026534).

#	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 LDLR-LOVD, British Heart Foundation, SCV000295162.2

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

#	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

From Revvity Omics, Revvity, SCV003831265.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022403.1

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

Description

NM_000527.4(LDLR): c.1049G>C (p.Arg350Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting, PP1_Moderate, PP4, and PS3 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: . PM2: This variant is absent from gnomAD (gnomAD v2.1.1). . PS4_Supporting: Variant meets PM2 and is identified in 5 index cases: 4 cases with DLCN criteria>=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case with DLCN criteria>=6 in Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France . PP1_Moderate: Variant segregates with FH phenotype in 5 informative meioses in 3 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). 3 relatives without the phenotype and the variant, 2 relatives with the phenotype and the variant . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6 after alternative causes of high cholesterol were excluded. Data is from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. . PS3_moderate: Level 2 assays: PMID 15100232 Heterologous cells (CHO) ACS, WB and NMR Spectroscopy <10% cell surface LDLR, 65% binding, (WB), ~10% expression

#	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: May 1, 2024

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