NM_000527.5(LDLR):c.818-2A>G AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 21, 2023
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:: RCV002519843.3

Allele description [Variation Report for NM_000527.5(LDLR):c.818-2A>G]

NM_000527.5(LDLR):c.818-2A>G

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.818-2A>G

HGVS:

NC_000019.10:g.11107390A>G
NG_009060.1:g.23010A>G
NM_000527.5:c.818-2A>GMANE SELECT
NM_001195798.2:c.818-2A>G
NM_001195799.2:c.695-2A>G
NM_001195800.2:c.314-2A>G
NM_001195803.2:c.437-2A>G
LRG_274t1:c.818-2A>G
LRG_274:g.23010A>G
NC_000019.9:g.11218066A>G
NM_000527.4:c.818-2A>G
c.818-2A>G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000125;

Molecular consequence:

NM_000527.5:c.818-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.818-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.695-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.314-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195803.2:c.437-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV003443155	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 25, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17765246, 16199547, 20809525, 28645073, 28492532
SCV003922711	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17765246, 20828696, 34456200, 27206941 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443155

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 25, 2022)

germline

clinical testing

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

SCV003922711

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 21, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV003443155.2

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 251471). Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 17765246). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922711.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: LDLR c.818-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to the retention of 10 nucleotides of intron 5 (Medeiros_2010). The variant was absent in 251436 control chromosomes (gnomAD). c.818-2A>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and has been shown to segregate with disease in affected families (Bourbon_2008, Jiang_2016, Kim_2022). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters including an expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was 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: Jun 23, 2024

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