NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 7, 2019
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:: RCV001050137.7

Allele description [Variation Report for NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr)]

NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr)

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.661G>T (p.Asp221Tyr)

Other names:

FH Finn-3; NM_000527.5(LDLR):c.661G>T

HGVS:

NC_000019.10:g.11105567G>T
NG_009060.1:g.21187G>T
NM_000527.5:c.661G>TMANE SELECT
NM_001195798.2:c.661G>T
NM_001195799.2:c.538G>T
NM_001195800.2:c.314-1825G>T
NM_001195803.2:c.314-998G>T
NP_000518.1:p.Asp221Tyr
NP_000518.1:p.Asp221Tyr
NP_001182727.1:p.Asp221Tyr
NP_001182728.1:p.Asp180Tyr
LRG_274t1:c.661G>T
LRG_274:g.21187G>T
LRG_274p1:p.Asp221Tyr
NC_000019.9:g.11216243G>T
NM_000527.4:c.661G>T
P01130:p.Asp221Tyr
c.661G>T

Protein change:

D180Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001792; UniProtKB: P01130#VAR_005333; dbSNP: rs875989906

NCBI 1000 Genomes Browser:

rs875989906

Molecular consequence:

NM_001195800.2:c.314-1825G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-998G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.661G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.661G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.538G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Mus musculus 15 days embryo head cDNA, RIKEN full-length enriched library, clone:D930049L19 product:zinc finger protein 354C, full insert sequence
gi|26352202|dbj|AK086760.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001214231	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 7, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7649546, 7573037, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001214231

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 7, 2019)

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

Screening for mutations in exon 4 of the LDL receptor gene in a German population with severe hypercholesterolemia.

Giesel J, Holzem G, Oette K.

Hum Genet. 1995 Sep;96(3):301-4.

PubMed [citation]

PMID:: 7649546

Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene.

Koivisto UM, Viikari JS, Kontula K.

Am J Hum Genet. 1995 Oct;57(4):789-97.

PubMed [citation]

PMID:: 7573037
PMCID:: PMC1801494

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001214231.4

#	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.Asp221 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID:¬†15523646,23375686,¬†11196104, 15241806, 220236128, 2698793, 25461735). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID:¬†9237502) and has been observed in individuals affected with this condition (PMID: 7649546, 7573037,¬†23375686, 10206683,¬†17765246, Invitae). This variant is also known as D200Y in the literature.¬† ClinVar contains an entry for this variant (Variation ID: 251356). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 221 of the LDLR protein (p.Asp221Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine.

#	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: Sep 1, 2024

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