NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 7, 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:: RCV001181335.8

Allele description [Variation Report for NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)]

NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)

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.542C>G (p.Pro181Arg)

HGVS:

NC_000019.10:g.11105448C>G
NG_009060.1:g.21068C>G
NM_000527.5:c.542C>GMANE SELECT
NM_001195798.2:c.542C>G
NM_001195799.2:c.419C>G
NM_001195800.2:c.314-1944C>G
NM_001195803.2:c.314-1117C>G
NP_000518.1:p.Pro181Arg
NP_000518.1:p.Pro181Arg
NP_001182727.1:p.Pro181Arg
NP_001182728.1:p.Pro140Arg
LRG_274t1:c.542C>G
LRG_274:g.21068C>G
LRG_274p1:p.Pro181Arg
NC_000019.9:g.11216124C>G
NM_000527.4:c.542C>G
c.542C>G
p.(Pro181Arg)

Protein change:

P140R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000361; dbSNP: rs557344672

NCBI 1000 Genomes Browser:

rs557344672

Molecular consequence:

NM_001195800.2:c.314-1944C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1117C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.542C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.542C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.419C>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

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
SCV001346460	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 503179, 540742, 583701, 11668640, 11754108, 20045108, 21310417, 21868016, 22698793, 23375686, 25647241, 32977124, 25741868
SCV001456144	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV003444822	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 7, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11754108, 16250003, 20045108, 22698793, 21868016, 25647241, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001346460

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 10, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV001456144

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

SCV003444822

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 7, 2023)

germline

clinical testing

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

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

Doctor's role not "pivotal" in Jonestown.

Glaser FB.

N Engl J Med. 1979 Dec 20;301(25):1401. No abstract available.

PubMed [citation]

PMID:: 503179

Intra-operative endoscopy of the total gastrointestinal tract in familial polyposis syndromes.

Webb WA.

Gastrointest Endosc. 1979 Nov;25(4):167. No abstract available.

PubMed [citation]

PMID:: 540742

See all PubMed Citations (15)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001346460.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This missense variant replaces proline with arginine at codon 181 of the LDLR protein. This variant is also known as p.Pro160Arg in the mature protein. This variant alters a conserved proline residue in the LDLR type A repeat 4 ligand binding domain of the LDLR protein (a.a. 146-186), where pathogenic missense variants are found enriched (ClinVar-LDLR). 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). Functional studies have shown that the variant interfered with LDLR precursor processing to the mature form, although the mature mutant protein exhibited wild-type like LDLR activity (PMID: 21868016, 25647241). This variant has been reported in at least ten individuals affected with familial hypercholesterolemia (PMID: 11668640, 11754108, 20045108, 21310417, 21868016, 22698793, 23375686, 32977124; ClinVar SCV000503179.1, SCV000583701.1, SCV000540742.1). It has also been reported in three individuals affected with early-onset myocardial infarction (PMID: 25647241). This variant has been identified in 6/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant 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

From Natera, Inc., SCV001456144.1

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003444822.2

#	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 proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 181 of the LDLR protein (p.Pro181Arg). This variant is present in population databases (rs557344672, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 11754108, 16250003, 20045108, 21868016, 22698793; Invitae). This variant is also known as P160R. ClinVar contains an entry for this variant (Variation ID: 183089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 21868016, 25647241). For these reasons, this variant has been classified as 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: Sep 29, 2024

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