NM_000527.5(LDLR):c.416A>G (p.Asp139Gly) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 22, 2024
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:: RCV000238588.6

Allele description [Variation Report for NM_000527.5(LDLR):c.416A>G (p.Asp139Gly)]

NM_000527.5(LDLR):c.416A>G (p.Asp139Gly)

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.416A>G (p.Asp139Gly)

HGVS:

NC_000019.10:g.11105322A>G
NG_009060.1:g.20942A>G
NM_000527.5:c.416A>GMANE SELECT
NM_001195798.2:c.416A>G
NM_001195799.2:c.293A>G
NM_001195800.2:c.314-2070A>G
NM_001195803.2:c.314-1243A>G
NP_000518.1:p.Asp139Gly
NP_000518.1:p.Asp139Gly
NP_001182727.1:p.Asp139Gly
NP_001182728.1:p.Asp98Gly
LRG_274t1:c.416A>G
LRG_274:g.20942A>G
LRG_274p1:p.Asp139Gly
NC_000019.9:g.11215998A>G
NM_000527.4:c.416A>G
c.416A>G

Protein change:

D139G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001727; dbSNP: rs879254518

NCBI 1000 Genomes Browser:

rs879254518

Molecular consequence:

NM_001195800.2:c.314-2070A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1243A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.416A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.416A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.293A>G - 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

Recent activity

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Fusarium verticillioides culture-collection BCCM/IHEM:23528 translation elongati...
Fusarium verticillioides culture-collection BCCM/IHEM:23528 translation elongation factor 1-alpha (TEF1a) gene, partial cds
gi|732560761|gb|KJ126413.1|

Nucleotide
xl11010H02F_1289296 Xenopus ORFeome version 1.0 library Xenopus laevis cDNA clon...
xl11010H02F_1289296 Xenopus ORFeome version 1.0 library Xenopus laevis cDNA clone xl11010H02 5', mRNA sequence
gi|798022330|gnl|dbEST|79641438|gb| 736.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294695	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,
SCV000503153	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]
SCV000583671	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]
SCV004834539	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20809525, 30270082, 34037665, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	1	not provided	2601	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

Mutational analysis of the LDLR gene in a cohort of Colombian families with familial hypercholesterolemia.

López G, Bernal LM, Gelvez N, Gómez LF, Nova A, Sánchez AI, Tamayo ML.

Atherosclerosis. 2018 Oct;277:434-439. doi: 10.1016/j.atherosclerosis.2018.08.052.

PubMed [citation]

PMID:: 30270082

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294695.2

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503153.1

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

Description

subject mutated among 2600 FH index cases screened = 1 / 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		1	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583671.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	1	not provided

From All of Us Research Program, National Institutes of Health, SCV004834539.1

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

Description

This missense variant replaces aspartic acid with glycine at codon 139 of the LDLR protein. This variant is also known as p.Asp118Gly in the mature protein. This variant alters a conserved aspartic acid residue in the LDLR type A repeat 3 of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 5 individuals affected with familial hypercholesterolemia (PMID: 20809525, 30270082; ClinVar SCV000583671.1, SCV000947750.3) and in one individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 30270082). This variant has not been identified 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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

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