NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jun 7, 2021
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:: RCV000211670.24

Allele description [Variation Report for NM_000527.5(LDLR):c.232C>T (p.Arg78Cys)]

NM_000527.5(LDLR):c.232C>T (p.Arg78Cys)

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.232C>T (p.Arg78Cys)

Other names:

NM_000527.5(LDLR):c.232C>T

HGVS:

NC_000019.10:g.11102705C>T
NG_009060.1:g.18325C>T
NM_000527.5:c.232C>TMANE SELECT
NM_001195798.2:c.232C>T
NM_001195799.2:c.190+2360C>T
NM_001195800.2:c.232C>T
NM_001195803.2:c.232C>T
NP_000518.1:p.Arg78Cys
NP_000518.1:p.Arg78Cys
NP_001182727.1:p.Arg78Cys
NP_001182729.1:p.Arg78Cys
NP_001182732.1:p.Arg78Cys
LRG_274t1:c.232C>T
LRG_274:g.18325C>T
NC_000019.9:g.11213381C>T
NM_000527.4(LDLR):c.232C>T
NM_000527.4:c.232C>T
P01130:p.Arg78Cys
c.232C>T

Protein change:

R78C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001629; UniProtKB: P01130#VAR_005307; dbSNP: rs370860696

NCBI 1000 Genomes Browser:

rs370860696

Molecular consequence:

NM_001195799.2:c.190+2360C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.232C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.232C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.232C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.232C>T - 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
SCV000268543	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Nov 29, 2010)	germline	clinical testing
SCV000294541	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] 9259195, 9664576 Citation Link,
SCV001960951	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Uncertain significance (Jun 7, 2021)	germline	curation	Citation Link,
SCV003816524	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820131	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9259195, 9664576, 24956927, 32522009, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	2	not provided	clinical testing, literature only
not provided	germline	unknown	6	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia.

Day IN, Whittall RA, O'Dell SD, Haddad L, Bolla MK, Gudnason V, Humphries SE.

Hum Mutat. 1997;10(2):116-27.

PubMed [citation]

PMID:: 9259195

Mutation analysis in familial hypercholesterolemia patients of different ancestries: identification of three novel LDLR gene mutations.

Callis M, Jansen S, Thiart R, de Villiers JN, Raal FJ, Kotze MJ.

Mol Cell Probes. 1998 Jun;12(3):149-52.

PubMed [citation]

PMID:: 9664576

See all PubMed Citations (5)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294541.2

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960951.1

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

Description

The NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001002 (0.010%) in South Asian exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 2 FH cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch Lipid Clinic score ≥ 6. PS4_supporting - Variant meets PM2. Variant identified in at least 4 unrelated index cases with Simon-Broome criteria for FH or Dutch Lipid Clinic score equal or above 6 from different labs.

#	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 Revvity Omics, Revvity, SCV003816524.2

#	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 All of Us Research Program, National Institutes of Health, SCV004820131.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant (also known as p.Arg57Cys in the mature protein) replaces arginine with cysteine at codon 78 of the LDLR protein. Computational prediction suggests that this variant may have a 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 individuals affected with familial hypercholesterolemia (PMID: 9259195, 9664576, 24956927, 32522009). This variant has been identified in 8/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		6	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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