NM_000527.5(LDLR):c.299A>G (p.Asp100Gly) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Apr 28, 2023
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:: RCV000237881.4

Allele description [Variation Report for NM_000527.5(LDLR):c.299A>G (p.Asp100Gly)]

NM_000527.5(LDLR):c.299A>G (p.Asp100Gly)

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.299A>G (p.Asp100Gly)

Other names:

NM_000527.5(LDLR):c.299A>G; p.Asp100Gly

HGVS:

NC_000019.10:g.11102772A>G
NG_009060.1:g.18392A>G
NM_000527.5:c.299A>GMANE SELECT
NM_001195798.2:c.299A>G
NM_001195799.2:c.190+2427A>G
NM_001195800.2:c.299A>G
NM_001195803.2:c.299A>G
NP_000518.1:p.Asp100Gly
NP_000518.1:p.Asp100Gly
NP_001182727.1:p.Asp100Gly
NP_001182729.1:p.Asp100Gly
NP_001182732.1:p.Asp100Gly
LRG_274t1:c.299A>G
LRG_274:g.18392A>G
LRG_274p1:p.Asp100Gly
NC_000019.9:g.11213448A>G
NM_000527.4:c.299A>G
c.299A>G

Protein change:

D100G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000783; dbSNP: rs879254460

NCBI 1000 Genomes Browser:

rs879254460

Molecular consequence:

NM_001195799.2:c.190+2427A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.299A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.299A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.299A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.299A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000294588	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000606067	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004022467	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Apr 28, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294588

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV000606067

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

no assertion criteria provided

Pathogenic

germline

research

SCV004022467

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Likely pathogenic
(Apr 28, 2023)

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	1	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation

Citations

PubMed

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294588.2

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

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606067.1

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022467.1

#	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.299A>G (p.Asp100Gly) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PP4, PS4_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: This variant is absent from gnomAD (gnomAD v2.1.1). - PP1: variant segregates with FH phenotype in 3 informative meiosis in 1 family from Laboratory of Genetics and Molecular Cardiology: 2 relatives with the phenotype and the variant and 1 relative without the phenotype and without the variant. - PP3: REVEL = 0.9. - PP4: Variant meets PM2 and is identified in at least 1 index case (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH), after alternative causes of high cholesterol were excluded. - PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH)

#	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: Aug 13, 2023

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