NM_000527.5(LDLR):c.970G>A (p.Gly324Ser) AND Hypercholesterolemia, familial, 1

Germline classification:: Benign (10 submissions)
Last evaluated:: Jun 23, 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:: RCV000237236.33

Allele description [Variation Report for NM_000527.5(LDLR):c.970G>A (p.Gly324Ser)]

NM_000527.5(LDLR):c.970G>A (p.Gly324Ser)

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.970G>A (p.Gly324Ser)

Other names:

NM_000527.5(LDLR):c.970G>A

HGVS:

NC_000019.10:g.11110681G>A
NG_009060.1:g.26301G>A
NM_000527.5:c.970G>AMANE SELECT
NM_001195798.2:c.970G>A
NM_001195799.2:c.847G>A
NM_001195800.2:c.466G>A
NM_001195803.2:c.589G>A
NP_000518.1:p.Gly324Ser
NP_000518.1:p.Gly324Ser
NP_001182727.1:p.Gly324Ser
NP_001182728.1:p.Gly283Ser
NP_001182729.1:p.Gly156Ser
NP_001182732.1:p.Gly197Ser
LRG_274t1:c.970G>A
LRG_274:g.26301G>A
LRG_274p1:p.Gly324Ser
NC_000019.9:g.11221357G>A
NM_000527.4:c.970G>A
c.970G>A

Protein change:

G156S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000640; dbSNP: rs72658860

Molecular consequence:

NM_000527.5:c.970G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.970G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.847G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.466G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.589G>A - 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
SCV000295119	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 11810272, 12436241, 9544746, 21722902 Citation Link,
SCV000503271	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)	Benign (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583771	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]
SCV001140984	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001285931	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Feb 13, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21722902, 9544746, 11810272, 12436241 Citation Link,
SCV001432674	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (May 23, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001960955	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Benign (Jun 23, 2021)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	10	2	not provided	2605	not provided	literature only, clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia.

Vaca G, Vàzquez A, Magaña MT, Ramìrez ML, Dàvalos IP, Martìnez E, Marìn B, Carrillo G.

Atherosclerosis. 2011 Oct;218(2):391-6. doi: 10.1016/j.atherosclerosis.2011.06.006. Epub 2011 Jun 13.

PubMed [citation]

PMID:: 21722902

Low density lipoprotein receptor mutations in a selected population of individuals with moderate hypercholesterolemia.

Arca M, Jokinen E.

Atherosclerosis. 1998 Jan;136(1):187-94.

PubMed [citation]

PMID:: 9544746

See all PubMed Citations (6)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295119.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (4)
2	not provided	1	not provided	not provided	literature only	PubMed (4)
3	not provided	1	not provided	not provided	literature only	PubMed (4)
4	not provided	1	not provided	not provided	literature only	PubMed (4)

Description

Reevaluation of the ACMG criteria for this entry: PP3, PS4, PP1, BS2 and BP2 can be scored. Therefore the classification is for Uncertain significance.

#	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
4	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, SCV000503271.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 2 / 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		2	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583771.2

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

Description

Dutch Lipid Clinic Scoring : Probable 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		3	not provided	2	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588536.1

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

Description

%MAF(ExAC):0.1163

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606286.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Iberoamerican FH Network, SCV000748045.1

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

Description

%MAF(ExAC):0.1163

#	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 Mendelics, SCV001140984.1

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

From Illumina Laboratory Services, Illumina, SCV001285931.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432674.1

#	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, SCV001960955.1

#	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.970G>A (p.Gly324Ser) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP2, PP1 and PP3) 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: BA1 - FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). BS2 - Identified in 4 heterozygous non-affected family members from different labs. BP2 - variant identified 1 index case with heterozygous FH phenotype who is double heterozygous with NM_000384.3(APOB):c.10580G>A p.Arg3527Gln (ClinVar ID 17890) - classified as Pathogenic by the general ACMG guidelines (Chora et al., 2018). PP1 - variant segregates with phenotype in 2 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL = 0.815. Variant has 1 stand alone, 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Benign, and only 2 Supporting codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign.

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000588536	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000606286	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None	Pathogenic	germline	research
SCV000748045	Iberoamerican FH Network	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000588536

Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 1, 2016)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV000606286

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

Pathogenic

germline

research

SCV000748045

Iberoamerican FH Network

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 1, 2016)

germline

research

PubMed (1)
[See all records that cite this PMID]

Last Updated: Jun 27, 2026

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