NM_000527.5(LDLR):c.1467C>G (p.Tyr489Ter) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 23, 2023
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:: RCV001207271.16

Allele description [Variation Report for NM_000527.5(LDLR):c.1467C>G (p.Tyr489Ter)]

NM_000527.5(LDLR):c.1467C>G (p.Tyr489Ter)

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.1467C>G (p.Tyr489Ter)

Other names:

NP_000518.1:p.Y489*

HGVS:

NC_000019.10:g.11113643C>G
NG_009060.1:g.29263C>G
NM_000527.5:c.1467C>GMANE SELECT
NM_001195798.2:c.1467C>G
NM_001195799.2:c.1344C>G
NM_001195800.2:c.963C>G
NM_001195803.2:c.1086C>G
NP_000518.1:p.Tyr489Ter
NP_000518.1:p.Tyr489Ter
NP_001182727.1:p.Tyr489Ter
NP_001182728.1:p.Tyr448Ter
NP_001182729.1:p.Tyr321Ter
NP_001182732.1:p.Tyr362Ter
LRG_274t1:c.1467C>G
LRG_274:g.29263C>G
LRG_274p1:p.Tyr489Ter
NC_000019.9:g.11224319C>G
NM_000527.4(LDLR):c.1467C>G
NM_000527.4:c.1467C>G
c.1467C>G
p.Tyr489Ter

Protein change:

Y321*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000415; dbSNP: rs370777955

NCBI 1000 Genomes Browser:

rs370777955

Molecular consequence:

NM_000527.5:c.1467C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.1467C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.1344C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.963C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.1086C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

Recent activity

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maltase-glucoamylase, intestinal isoform X3 [Delphinapterus leucas]
maltase-glucoamylase, intestinal isoform X3 [Delphinapterus leucas]
gi|1246147653|ref|XP_022435021.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001378615	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 23, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7833932, 25487149, 20809525, 28645073, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001378615

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 23, 2023)

germline

clinical testing

PubMed (5)
[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

Detection of a novel mutation (stop 468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.

Simard J, Moorjani S, Vohl MC, Couture P, Torres AL, Gagné C, Després JP, Labrie F, Lupien PJ.

Hum Mol Genet. 1994 Sep;3(9):1689-91. No abstract available.

PubMed [citation]

PMID:: 7833932

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL; NHLBI Exome Sequencing Project., Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AF, et al.

Nature. 2015 Feb 5;518(7537):102-6. doi: 10.1038/nature13917. Epub 2014 Dec 10.

PubMed [citation]

PMID:: 25487149
PMCID:: PMC4319990

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001378615.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is also known as stop 468. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 161270). This premature translational stop signal has been observed in individual(s) with FH and clinical features of familial hypercholesterolemia (FH) (PMID: 7833932, 25487149). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs370777955, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr489*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).

#	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: Oct 26, 2024

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