NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Jun 9, 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:: RCV000238217.15

Allele description [Variation Report for NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)]

NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)

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.1576C>T (p.Pro526Ser)

Other names:

FH Cincinnati-3; NM_000527.5(LDLR):c.1576C>T

HGVS:

NC_000019.10:g.11113752C>T
NG_009060.1:g.29372C>T
NM_000527.5:c.1576C>TMANE SELECT
NM_001195798.2:c.1576C>T
NM_001195799.2:c.1453C>T
NM_001195800.2:c.1072C>T
NM_001195803.2:c.1195C>T
NP_000518.1:p.Pro526Ser
NP_000518.1:p.Pro526Ser
NP_001182727.1:p.Pro526Ser
NP_001182728.1:p.Pro485Ser
NP_001182729.1:p.Pro358Ser
NP_001182732.1:p.Pro399Ser
LRG_274t1:c.1576C>T
LRG_274:g.29372C>T
LRG_274p1:p.Pro526Ser
NC_000019.9:g.11224428C>T
NM_000527.4:c.1576C>T
P01130:p.Pro526Ser
c.1576C>T

Protein change:

P358S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000076; UniProtKB: P01130#VAR_005396; dbSNP: rs730882106

NCBI 1000 Genomes Browser:

rs730882106

Molecular consequence:

NM_000527.5:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1453C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1072C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536] - Comment(s)

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
SCV000295505	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 11462246, 1301956, 9259195 Citation Link,
SCV000503367	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583850	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000680104	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	no assertion criteria provided (ACMG Guidelines, 2015)	Likely pathogenic (May 29, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432657	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 3, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001960928	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Uncertain significance (Jun 9, 2021)	germline	curation	Citation Link,
SCV004822480	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1301956, 9259195, 10208479, 11462246, 25647241, 27497240, 31345425, 34037665, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	12	3	not provided	2604	not provided	clinical testing, literature only, research
not provided	germline	unknown	7	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

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

See all PubMed Citations (9)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295505.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (3)
2	not provided	1	not provided	not provided	literature only	PubMed (3)
3	not provided	1	not provided	not provided	literature only	PubMed (3)

#	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
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503367.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 4 , family members = 3 / FH-Cincinnati-3, 5% to 15% LDLR Activity / Software predictions: Damaging

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		4	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583850.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#	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		4	not provided	3	not provided

From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000680104.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432657.1

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960928.1

#	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.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) 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 = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,952. PP4 - Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195). PS4_supporting - Variant meets PM2. Variant identified in 5 index cases.

#	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, SCV004822480.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro505Ser in the mature protein; FH Cincinnati-3. 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). A functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). Another functional study has shown significantly reduced LDLR activity (5-15% of the wild type) in cells from an individual with heterozygous hypercholesterolemia (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 10208479, 11462246, 27497240, 31345425, 34037665; Color internal data). This variant has been identified in 3/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the 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	108544	not provided	not provided		7	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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