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

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jul 27, 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:: RCV001181333.20

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]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001346457	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9259195, 9664576, 24956927, 32522009, 25741868
SCV001416327	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 2, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9237502, 9259195, 9664576, 22883975, 22910581, 24956927, 28492532
SCV001422745	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 27680772, 22910581, 29353225, 24956927, 22883975, 28502495, 9664576, 11845603, 9259195, 25741868 Citation Link,
SCV002086360	Natera, Inc.	no assertion criteria provided	Uncertain significance (Mar 7, 2020)	germline	clinical testing

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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

Citations

PubMed

Familial Hypercholesterolemia in a Healthy Elderly Population.

Lacaze P, Sebra R, Riaz M, Hooper AJ, Tiller J, Bakshi A, Woods RL, Tonkin AM, Reid CM, Murray AM, Nicholls SJ, Watts GF, Schadt E, McNeil JJ.

Circ Genom Precis Med. 2020 Aug;13(4):e002938. doi: 10.1161/CIRCGEN.120.002938. Epub 2020 Jun 10. No abstract available.

PubMed [citation]

PMID:: 32522009
PMCID:: PMC7442644

CpG hotspot mutations at the LDL receptor locus are a frequent cause of familial hypercholesterolaemia among South African Indians.

Kotze MJ, Loubser O, Thiart R, de Villiers JN, Langenhoven E, Theart L, Steyn K, Marais AD, Raal FJ.

Clin Genet. 1997 Jun;51(6):394-8.

PubMed [citation]

PMID:: 9237502

See all PubMed Citations (13)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001346457.3

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001416327.2

#	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 with cysteine at codon 78 of the LDLR protein (p.Arg78Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs370860696, ExAC 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9237502, 9259195, 9664576, 22883975, 22910581, 24956927). This variant is also known as R57C. ClinVar contains an entry for this variant (Variation ID: 161289). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422745.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

Description

The p.Arg78Cys variant in LDLR has been reported in at least 9 individuals with familial hypercholesterolemia (PMID: 9259195, 28502495, 11845603, 9664576, 22883975, 24956927, 27680772) and has been Identified in 0.01002% (2/19952) of East Asian chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs370860696). This variant has also been reported in ClinVar (VariationID: 161289) as likely pathogenic by the British Heart Foundation, pathogenic by Fiona Stanley Hospital, and as a VUS by the University of Washington Medical Center. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate (Richards 2015).

#	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 Natera, Inc., SCV002086360.1

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

Last Updated: Oct 13, 2024

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