NM_000527.5(LDLR):c.2389+2T>G AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 28, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000238361.4

Allele description [Variation Report for NM_000527.5(LDLR):c.2389+2T>G]

NM_000527.5(LDLR):c.2389+2T>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.2389+2T>G

Other names:

IVS16 ds T-G +2

HGVS:

NC_000019.10:g.11128087T>G
NG_009060.1:g.43707T>G
NM_000527.5:c.2389+2T>GMANE SELECT
NM_001195798.2:c.2389+2T>G
NM_001195799.2:c.2266+2T>G
NM_001195800.2:c.1885+2T>G
NM_001195803.2:c.1855+2T>G
LRG_274t1:c.2389+2T>G
LRG_274:g.43707T>G
NC_000019.9:g.11238763T>G
NM_000527.4:c.2389+2T>G
c.2389+2T>G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000733; dbSNP: rs879255188

NCBI 1000 Genomes Browser:

rs879255188

Molecular consequence:

NM_000527.5:c.2389+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.2389+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.2266+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.1885+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.1855+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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actin-binding protein WASF2 isoform 1 [Homo sapiens]
actin-binding protein WASF2 isoform 1 [Homo sapiens]
gi|11386183|ref|NP_008921.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295972	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000484794	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432565	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 21, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV002568020	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Aug 28, 2022)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	2	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia.

Taylor A, Tabrah S, Wang D, Sozen M, Duxbury N, Whittall R, Humphries SE, Norbury G.

Clin Genet. 2007 Jun;71(6):561-8.

PubMed [citation]

PMID:: 17539906

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27765764

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295972.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

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

From Robarts Research Institute, Western University, SCV000484794.1

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

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432565.1

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

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002568020.1

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

Description

The NM_000527.5(LDLR):c.2389+2T>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1_Strong, PP1_moderate, PM2, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - variant is at +2 donor splice site, and is predicted to lead to exon 16 skipping. Exon 16 is in frame, so PVS1_Strong is met. PP1_moderate - variant segregates with FH phenotype in 5 relatives from Robarts Research Institute, so PP1_Moderate is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PS4_Supporting - variant meets PM2 and is identified in 3 unrelated index cases, after alternative causes of hypercholesterolemia were excluded, from different labs (1 with DLCN >=6 from Robarts Research Institute, 1 with possible FH according to Simon-Broome criteria from PMID 17539906 (UK) and 1 with DLCN >=6 from PMID 33418990 (Russia)), so PS4_Supporting is met. PP4 - variant meets PM2 and is identified in 3 unrelated index cases from different labs (see PS4 for details), so PP4 is met.

#	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: Aug 5, 2023

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