NM_000527.5(LDLR):c.1056_1060+3del AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001820791.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1056_1060+3del]

NM_000527.5(LDLR):c.1056_1060+3del

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.1056_1060+3del

HGVS:

NC_000019.10:g.11110767_11110774del
NG_009060.1:g.26387_26394del
NM_000527.5:c.1056_1060+3delMANE SELECT
NM_001195798.2:c.1056_1060+3del
NM_001195799.2:c.933_937+3del
NM_001195800.2:c.552_556+3del
NM_001195803.2:c.675_679+3del
LRG_274t1:c.1056_1060+3del
LRG_274:g.26387_26394del
NC_000019.9:g.11221441_11221448del
NC_000019.9:g.11221443_11221450del
NC_000019.9:g.11221443_11221450delCGAAGGTG
NM_000527.4:c.1056_1060+3del
NM_000527.4:c.1056_1060+3delCGAAGGTG
c.1056_1060+3del
p.?
p.Cys352*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000666; dbSNP: rs879254770

NCBI 1000 Genomes Browser:

rs879254770

Molecular consequence:

NM_000527.5:c.1056_1060+3del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.1056_1060+3del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.933_937+3del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.552_556+3del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.675_679+3del - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002064181	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 20, 2024)	germline	clinical testing	Citation Link,
SCV002502292	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 11, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16389549, 30586733, 34037665, 31447099, 25741868
SCV004219934	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Apr 13, 2023)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 34363016, 34037665, 32220565, 30586733, 28008010, 16389549, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002064181

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Sep 20, 2024)

germline

clinical testing

Citation Link,

SCV002502292

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 11, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004219934

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Apr 13, 2023)

unknown

clinical testing

PubMed (7)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.

eMERGE Consortium. Electronic address: agibbs@bcm.edu.; eMERGE Consortium..

Am J Hum Genet. 2019 Sep 5;105(3):588-605. doi: 10.1016/j.ajhg.2019.07.018. Epub 2019 Aug 22.

PubMed [citation]

PMID:: 31447099
PMCID:: PMC6731372

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV002064181.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Identified in a patient with early onset myocardial infarction in published literature (PMID: 30586733); Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31447099, 28008010, 34037665, 32220565, 34363016, 16389549, 37589137, 30586733)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002502292.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219934.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The LDLR c.1056_1060+3del variant disrupts a canonical splice-donor site and interferes with normal LDLR mRNA splicing. It is also predicted to create a premature stop codon (p.Cys352*) that may disrupt normal LDLR protein synthesis. The frequency of this variant in the general population, 0.000032 (1/31382 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals with clinical features of familial hypercholesterolemia (PMIDs: 34363016 (2021), 34037665 (2021), 32220565 (2020), 30586733 (2019), 28008010 (2016), 16389549 (2006)). Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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