NM_000527.5(LDLR):c.1864G>A (p.Asp622Asn) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 4, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000812951.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1864G>A (p.Asp622Asn)]

NM_000527.5(LDLR):c.1864G>A (p.Asp622Asn)

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.1864G>A (p.Asp622Asn)

HGVS:

NC_000019.10:g.11120110G>A
NG_009060.1:g.35730G>A
NM_000527.5:c.1864G>AMANE SELECT
NM_001195798.2:c.1864G>A
NM_001195799.2:c.1741G>A
NM_001195800.2:c.1360G>A
NM_001195803.2:c.1483G>A
NP_000518.1:p.Asp622Asn
NP_000518.1:p.Asp622Asn
NP_001182727.1:p.Asp622Asn
NP_001182728.1:p.Asp581Asn
NP_001182729.1:p.Asp454Asn
NP_001182732.1:p.Asp495Asn
LRG_274t1:c.1864G>A
LRG_274:g.35730G>A
LRG_274p1:p.Asp622Asn
NC_000019.9:g.11230786G>A
NM_000527.4:c.1864G>A
c.1864G>A

Protein change:

D454N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000909; dbSNP: rs879255059

NCBI 1000 Genomes Browser:

rs879255059

Molecular consequence:

NM_000527.5:c.1864G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1864G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1741G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1360G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1483G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000953281	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 4, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15701167, 27824480, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000953281

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 4, 2018)

germline

clinical testing

PubMed (3)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia.

Zakharova FM, Damgaard D, Mandelshtam MY, Golubkov VI, Nissen PH, Nilsen GG, Stenderup A, Lipovetsky BM, Konstantinov VO, Denisenko AD, Vasilyev VB, Faergeman O.

BMC Med Genet. 2005 Feb 8;6:6.

PubMed [citation]

PMID:: 15701167
PMCID:: PMC551615

The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.

Gabčová D, Vohnout B, Staníková D, Hučková M, Kadurová M, Debreová M, Kozárová M, Fábryová Ľ, Staník J, Klimeš I, Rašlová K, Gašperiková D.

Physiol Res. 2017 Mar 31;66(1):75-84. Epub 2016 Nov 8.

PubMed [citation]

PMID:: 27824480

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000953281.4

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp662 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID:¬†15701167, 16159606,¬†22698793), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change decreases LDL binding and uptake (PMID:¬†28645073). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 15701167, 27824480,¬†28645073,¬†22698793,¬†Invitae. This variant is also known as p.D601N in the literature. ClinVar contains an entry for this variant (Variation ID: 252092). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 622 of the LDLR protein (p.Asp622Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine.

#	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: Apr 6, 2024

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