NM_000527.5(LDLR):c.2500del (p.Asp834fs) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 6, 2020
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:: RCV001390890.7

Allele description [Variation Report for NM_000527.5(LDLR):c.2500del (p.Asp834fs)]

NM_000527.5(LDLR):c.2500del (p.Asp834fs)

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.2500del (p.Asp834fs)

HGVS:

NC_000019.10:g.11129623del
NG_009060.1:g.45243del
NM_000527.5:c.2500delMANE SELECT
NM_001195798.2:c.2500del
NM_001195799.2:c.2377del
NM_001195800.2:c.1996del
NM_001195803.2:c.1966del
NP_000518.1:p.Asp834fs
NP_000518.1:p.Asp834fs
NP_001182727.1:p.Asp834fs
NP_001182728.1:p.Asp793fs
NP_001182729.1:p.Asp666fs
NP_001182732.1:p.Asp656fs
LRG_274t1:c.2500del
LRG_274:g.45243del
LRG_274p1:p.Asp834fs
NC_000019.9:g.11240298del
NC_000019.9:g.11240299del
NM_000527.4:c.2500del
NM_000527.4:c.2500delG

Protein change:

D656fs

Links:

dbSNP: rs1555809594

NCBI 1000 Genomes Browser:

rs1555809594

Molecular consequence:

NM_000527.5:c.2500del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.2500del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.2377del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.1996del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195803.2:c.1966del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Familial hypercholesterolemia
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
SCV001592756	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 6, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26892515, 11933210, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001592756

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 6, 2020)

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

The genetic spectrum of familial hypercholesterolemia in south-eastern Poland.

Sharifi M, Walus-Miarka M, Idzior-Waluś B, Malecki MT, Sanak M, Whittall R, Li KW, Futema M, Humphries SE.

Metabolism. 2016 Mar;65(3):48-53. doi: 10.1016/j.metabol.2015.10.018. Epub 2015 Nov 10.

PubMed [citation]

PMID:: 26892515
PMCID:: PMC4766367

Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations.

Salazar LA, Hirata MH, Cavalli SA, Nakandakare ER, Forti N, Diament J, Giannini SD, Bertolami MC, Hirata RD.

Hum Mutat. 2002 Apr;19(4):462-3.

PubMed [citation]

PMID:: 11933210

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001592756.4

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

Description

This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 440700). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the LDLR protein. Other variant(s) that disrupt this region (p.Ser849*) have been determined to be pathogenic (PMID: 26892515, 11933210, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the LDLR gene (p.Asp834Metfs*95). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acids of the LDLR protein and extend the protein by an additional 67 amino acids.

#	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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