NM_000527.5(LDLR):c.313_313+1del AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Feb 2, 2022
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:: RCV000211607.12

Allele description [Variation Report for NM_000527.5(LDLR):c.313_313+1del]

NM_000527.5(LDLR):c.313_313+1del

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.313_313+1del

Other names:

FH Lille

HGVS:

NC_000019.10:g.11102786_11102787del
NG_009060.1:g.18406_18407del
NM_000527.4(LDLR):c.313_313+1delCG
NM_000527.5:c.313_313+1delMANE SELECT
NM_001195798.2:c.313_313+1del
NM_001195799.2:c.191-2434_191-2433del
NM_001195800.2:c.313_313+1del
NM_001195803.2:c.313_313+1del
LRG_274t1:c.313_313+1del
LRG_274:g.18406_18407del
NC_000019.10:g.11102786_11102787delCG
NC_000019.9:g.11213462_11213463del
NM_000527.4(LDLR):c.313_313+1delCG
NM_000527.4:c.313_313+1del
NM_000527.4:c.313_313+1delCG
NM_000527.5:c.313_313+1del
c.313_313+1del
p.Lys107Argfs*99

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001692; dbSNP: rs875989896

NCBI 1000 Genomes Browser:

rs875989896

Molecular consequence:

NM_001195799.2:c.191-2434_191-2433del - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.313_313+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.313_313+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.313_313+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.313_313+1del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268553	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jul 9, 2008)	germline	clinical testing
SCV000294601	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000503130	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]
SCV000583653	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34906454, 25741868
SCV000599324	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000987703	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580841	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	19	8	not provided	2601	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification.

Chora JR, Iacocca MA, Tichý L, Wand H, Kurtz CL, Zimmermann H, Leon A, Williams M, Humphries SE, Hooper AJ, Trinder M, Brunham LR, Costa Pereira A, Jannes CE, Chen M, Chonis J, Wang J, Kim S, Johnston T, Soucek P, Kramarek M, Leigh SE, et al.

Genet Med. 2022 Feb;24(2):293-306. doi: 10.1016/j.gim.2021.09.012. Epub 2021 Nov 30.

PubMed [citation]

PMID:: 34906454

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

See all PubMed Citations (3)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268553.1

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

#	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 LDLR-LOVD, British Heart Foundation, SCV000294601.2

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503130.1

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

Description

subjects mutated among 2600 FH index cases screened = 2 , family members = 2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		2	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583653.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	PubMed (2)

Description

Dutch Lipid Clinic Scoring : Definite FH

Description

Updated according to ClinGen VCEP Guidelines (2022) for LDLR variant classification in FH (PMID: 34906454). This frameshift mutation is estimated to generate truncated protein products deprived of most of their functional domains (PVS1). In addition, this deletion abolishes the canonical donor splice site of intron 3, without potentially creating any alternate donor splice site in close vicinity (PP3). It was shown by in-vitro studies (PS3 moderate) to abolish protein expression in homozygous carriers (FH Lille Allele). Mutation recurrently causing FH diagnosed by validated clinical criteria reported in multiple Disease Specific Databases for several decades (PS4) . Absent from Large General Population Databases (PM2 Strong). More than 10 index cases from the Lille registry had a clinical scoring of Definite FH (DLCN Score >8). This clinical scoring level is highly specific (90%) for a carrier status of a pathogenic LDLR mutation causative of FH (PP4 Strong).

#	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		14	not provided	8	not provided

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599324.1

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

Description

"Assay Description:Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	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
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987703.1

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

From MGZ Medical Genetics Center, SCV002580841.1

#	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

Last Updated: Sep 1, 2024

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