NM_000527.5(LDLR):c.1392del (p.Tyr465fs) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 28, 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:: RCV001034625.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1392del (p.Tyr465fs)]

NM_000527.5(LDLR):c.1392del (p.Tyr465fs)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1392del (p.Tyr465fs)

HGVS:

NC_000019.10:g.11113568del
NG_009060.1:g.29188del
NM_000527.5:c.1392delMANE SELECT
NM_001195798.2:c.1392del
NM_001195799.2:c.1269del
NM_001195800.2:c.888del
NM_001195803.2:c.1011del
NP_000518.1:p.Tyr465fs
NP_001182727.1:p.Tyr465fs
NP_001182728.1:p.Tyr424fs
NP_001182729.1:p.Tyr297fs
NP_001182732.1:p.Tyr338fs
LRG_274:g.29188del
NC_000019.9:g.11224244del
NC_000019.9:g.11224244delC
NM_000527.4:c.1392delC
c.1392delC

Protein change:

Y297fs

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000732; dbSNP: rs879254888

NCBI 1000 Genomes Browser:

rs879254888

Molecular consequence:

NM_000527.5:c.1392del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.1392del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.888del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195803.2:c.1011del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Homo sapiens calcium/calmodulin dependent protein kinase II beta (CAMK2B), transcript variant 5, mRNA
gi|1675172957|ref|NM_172081.3|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000817307	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 28, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16250003, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000817307

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 28, 2019)

germline

clinical testing

PubMed (2)
[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

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000817307.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Tyr465Metfs*42) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant was reported in an individual affected with familial hypercholesterolemia (PMID: 16250003) note, that this publication erroneously reported the protein effect at this position as p.Asp464GlufsX18. ClinVar contains an entry for this variant (Variation ID: 251825). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.

#	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 29, 2024

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