NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 14, 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:: RCV000985772.14

Allele description [Variation Report for NM_000527.5(LDLR):c.910G>A (p.Asp304Asn)]

NM_000527.5(LDLR):c.910G>A (p.Asp304Asn)

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.910G>A (p.Asp304Asn)

Other names:

D283N; FH Denver 2; NM_000527.5(LDLR):c.910G>A

HGVS:

NC_000019.10:g.11107484G>A
NG_009060.1:g.23104G>A
NM_000527.5:c.910G>AMANE SELECT
NM_001195798.2:c.910G>A
NM_001195799.2:c.787G>A
NM_001195800.2:c.406G>A
NM_001195803.2:c.529G>A
NP_000518.1:p.Asp304Asn
NP_000518.1:p.Asp304Asn
NP_001182727.1:p.Asp304Asn
NP_001182728.1:p.Asp263Asn
NP_001182729.1:p.Asp136Asn
NP_001182732.1:p.Asp177Asn
LRG_274t1:c.910G>A
LRG_274:g.23104G>A
LRG_274p1:p.Asp304Asn
NC_000019.9:g.11218160G>A
NM_000527.4:c.910G>A
P01130:p.Asp304Asn
c.910G>A

Protein change:

D136N; ASP283ASN

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001861; UniProtKB: P01130#VAR_005355; OMIM: 606945.0008; dbSNP: rs121908030

NCBI 1000 Genomes Browser:

rs121908030

Molecular consequence:

NM_000527.5:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.787G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.406G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001134272	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Feb 5, 2019)	unknown	clinical testing	PubMed (19) [See all records that cite these PMIDs] 9664576, 11810272, 12436241, 2088165, 21418584, 22698793, 1301956, 25637381, 25487149, 24507775, 23064986, 27678436, 30795984, 31048103, 31447099, 32719484, 33740630, 34037665, 26467025
SCV002028774	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 14, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001134272

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Feb 5, 2019)

unknown

clinical testing

PubMed (19)
[See all records that cite these PMIDs]

SCV002028774

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 14, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation analysis in familial hypercholesterolemia patients of different ancestries: identification of three novel LDLR gene mutations.

Callis M, Jansen S, Thiart R, de Villiers JN, Raal FJ, Kotze MJ.

Mol Cell Probes. 1998 Jun;12(3):149-52.

PubMed [citation]

PMID:: 9664576

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

See all PubMed Citations (19)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134272.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

The frequency of this variant in the general population, 0.00012 (3/24946 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant was identified in multiple individuals affected with hypercholesterolemia (PMID: 11810272 (2001), 12436241 (2002), 21418584 (2011), 22698793 (2012), 23064986 (2012), 24507775 (2014), 33740630 (2021), 34037665 (2021)). The variant has also been reported as compound heterozygous with another pathogenic variant in children with a severe presentation (PMID: 27678436 (2016), 30795984 (2019)). Functional studies of homozygous cultured fibroblasts showed a retention of only 5-15% LDLR activity (PMID: 1301956 (1992)). Based on the available information, this variant is classified as pathogenic.

#	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 GeneDx, SCV002028774.3

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

Description

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; Published functional studies demonstrate significantly reduced LDL receptor activity compared to wild type (Hobbs et al., 1990; Hobbs et al., 1992); Also known as FH Denver-2 and p.D283N; This variant is associated with the following publications: (PMID: 2318961, 12436241, 31447099, 25637381, 25487149, 24507775, 2088165, 9664576, 11810272, 17094996, 21418584, 22698793, 34037665, 30795984, 1301956, 33740630, 32719484)

#	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

Last Updated: Nov 3, 2024

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