NM_000527.5(LDLR):c.1186+5G>C AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 24, 2023
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:: RCV000417292.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1186+5G>C]

NM_000527.5(LDLR):c.1186+5G>C

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.1186+5G>C

HGVS:

NC_000019.10:g.11111644G>C
NG_009060.1:g.27264G>C
NM_000527.5:c.1186+5G>CMANE SELECT
NM_001195798.2:c.1186+5G>C
NM_001195799.2:c.1063+5G>C
NM_001195800.2:c.682+5G>C
NM_001195803.2:c.805+5G>C
LRG_274t1:c.1186+5G>C
LRG_274:g.27264G>C
NC_000019.9:g.11222320G>C
NM_000527.4:c.1186+5G>C

Links:

dbSNP: rs879254821

NCBI 1000 Genomes Browser:

rs879254821

Molecular consequence:

NM_000527.5:c.1186+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1186+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.1063+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.682+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.805+5G>C - intron variant - [Sequence Ontology: SO:0001627]

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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gi|1919575220|ref|NC_050975.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000503310	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432547	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 21, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV004022397	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Mar 24, 2023)	germline	curation	Citation Link,
SCV004836235	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31345425, 32220565, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	2601	not provided	clinical testing, research
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

Trinder M, Li X, DeCastro ML, Cermakova L, Sadananda S, Jackson LM, Azizi H, Mancini GBJ, Francis GA, Frohlich J, Brunham LR.

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.

PubMed [citation]

PMID:: 31345425

Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia.

Brown EE, Byrne KH, Davis DM, McClellan R, Leucker T, Jones SR, Martin SS.

J Clin Lipidol. 2020 May - Jun;14(3):331-338. doi: 10.1016/j.jacl.2020.02.006. Epub 2020 Mar 2.

PubMed [citation]

PMID:: 32220565

See all PubMed Citations (3)

Details of each submission

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503310.1

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

Description

subject mutated among 2600 FH index cases screened = 1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		1	not provided	not provided	not provided

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432547.1

#	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, SCV004022397.1

#	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.1186+5G>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMaxMAF = 0.0000809 in African/African American population in gnomAD (gnomAD v2.1.1). The PopMax is African/African American for this variant. However the allele number at this position for 19-11222320-G-C is 2 / 8710, which is < 10,000 in total and only genome data is available. Exome data from a neighboring variant 19-11222323-C-T, allele number 15994, was used for PopMaxMAF calculation: PopMaxMAF = 2 / (15994 + 8710) = 0.0000809 in African/African American population PP3: Variant is located within canonical intron 8 donor motif, splicing prediction is performed using MES: Wild type canonical donor motif tggGTGAGC score = 7.23, Variant canonical donor motif tggGTGACC score = 0.50, Var Score/Wt Score Ratio = 0.0692 which is <0.8, therefore PP3 is met. Predicted impact for alternative splicing caused by this variant is also confirmed by SpliceAI. PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for possible FH and DLCN score = 6 (PMID 32220565, Table 2), after alternative causes of high cholesterol were excluded, reported by Brown et al, 2020, from Johns Hopkins University, US. PS3 not met: Functional data is not available.

#	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 All of Us Research Program, National Institutes of Health, SCV004836235.1

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

Description

This variant causes a G to C nucleotide substitution at the +5 position of intron 8 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 31345425, 32220565). This variant has been identified in 2/31392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same splice site, c.1186+5G>A, is considered to be disease-causing (ClinVar variation ID: 251706). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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