NM_000527.5(LDLR):c.681C>G (p.Asp227Glu) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 26, 2022
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:: RCV001823092.9

Allele description [Variation Report for NM_000527.5(LDLR):c.681C>G (p.Asp227Glu)]

NM_000527.5(LDLR):c.681C>G (p.Asp227Glu)

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.681C>G (p.Asp227Glu)

Other names:

D206E; FH Afrikaner 1; FH Maine; FH Afrikaner-1; NP_000518.1:p.D227E

HGVS:

NC_000019.10:g.11105587C>G
NG_009060.1:g.21207C>G
NM_000527.5:c.681C>GMANE SELECT
NM_001195798.2:c.681C>G
NM_001195799.2:c.558C>G
NM_001195800.2:c.314-1805C>G
NM_001195803.2:c.314-978C>G
NP_000518.1:p.Asp227Glu
NP_000518.1:p.Asp227Glu
NP_001182727.1:p.Asp227Glu
NP_001182728.1:p.Asp186Glu
LRG_274t1:c.681C>G
LRG_274:g.21207C>G
LRG_274p1:p.Asp227Glu
NC_000019.9:g.11216263C>G
NM_000527.4:c.681C>G
NM_001195798.1:c.681C>G
P01130:p.Asp227Glu
c.681C>G
p.(Asp227Glu)

Protein change:

D186E; ASP206GLU

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001815; UniProtKB: P01130#VAR_005338; OMIM: 606945.0006; dbSNP: rs121908028

NCBI 1000 Genomes Browser:

rs121908028

Molecular consequence:

NM_001195800.2:c.314-1805C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-978C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.681C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.681C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.558C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002072680	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 17, 2022)	germline	clinical testing	Citation Link,
SCV002103274	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 21, 2021)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 2569482, 2352257, 21310417, 23375686, 27680772, 23669246, 22883975, 17539906, 21382890, 32041611, 6324732, 3202825, 1301956, 1463746, 25741868
SCV002501901	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 26, 2022)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 2569482, 23375686, 32977124, 30592178, 32041611, 33740630, 31048103, 28965616, 34037665, 29284604, 30270076, 32922439, 33087929, 31447099, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002072680

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 17, 2022)

germline

clinical testing

Citation Link,

SCV002103274

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 21, 2021)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV002501901

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 26, 2022)

germline

clinical testing

PubMed (15)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics.

Kotze MJ, Warnich L, Langenhoven E, du Plessis L, Retief AE.

J Med Genet. 1990 May;27(5):298-302.

PubMed [citation]

PMID:: 2352257
PMCID:: PMC1017079

An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia.

Dušková L, Kopečková L, Jansová E, Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2011 May;216(1):139-45. doi: 10.1016/j.atherosclerosis.2011.01.023. Epub 2011 Jan 21.

PubMed [citation]

PMID:: 21310417

See all PubMed Citations (26)

Details of each submission

From GeneDx, SCV002072680.2

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

Description

Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL- receptor class A5 repeat domain that is critical for ligand binding (Schneider et al., 2003); Functional studies demonstrate a damaging effect: creation of two LDLR isoforms, both with a slower maturation process, and one with inability to bind to the lipoprotein ligand resulting in a reduced rate of lipoprotein degradation (Leitersdorf et al., 1989; Fourie et al., 1992); Common founder variant in the Afrikaner population (Kotze et al., 1993); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 3202825, 2352257, 23375686, 2569482, 11810272, 26892515, 8093663, 9664576, 17087781, 2565980, 1463746, 30270076, 31048103, 29284604, 31447099, 32977124, 32041611, 32922439, 33740630, 34037665, 33087929, 28965616, 30592178, 27680772, 12827279, 3430554, 8399083)

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV002103274.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

PS1, PS3, PS4, PM1, PM2, PM3, PM5, PP3

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002501901.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (15)

#	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		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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