NM_000527.5(LDLR):c.820del (p.Thr274fs) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 7, 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:: RCV000408879.7

Allele description [Variation Report for NM_000527.5(LDLR):c.820del (p.Thr274fs)]

NM_000527.5(LDLR):c.820del (p.Thr274fs)

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.820del (p.Thr274fs)

HGVS:

NC_000019.10:g.11107394del
NG_009060.1:g.23014del
NM_000527.5:c.820delMANE SELECT
NM_001195798.2:c.820del
NM_001195799.2:c.697del
NM_001195800.2:c.316del
NM_001195803.2:c.439del
NP_000518.1:p.T274Hfs*95
NP_000518.1:p.Thr274fs
NP_001182727.1:p.Thr274fs
NP_001182728.1:p.Thr233fs
NP_001182729.1:p.Thr106fs
NP_001182732.1:p.Thr147fs
LRG_274:g.23014del
NC_000019.10:g.11107394delA
NC_000019.9:g.11218070del
NC_000019.9:g.11218070delA
NM_000527.4:c.820delA
NM_000527.5:c.820del
p.Thr274HisfsX96

Protein change:

T106fs

Links:

dbSNP: rs751122998

NCBI 1000 Genomes Browser:

rs751122998

Molecular consequence:

NM_000527.5:c.820del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.820del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.697del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.316del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195803.2:c.439del - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

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heterogeneous nuclear ribonucleoprotein A1 isoform a [Homo sapiens]
heterogeneous nuclear ribonucleoprotein A1 isoform a [Homo sapiens]
gi|4504445|ref|NP_002127.1|

Protein
histone H2A.V isoform 4 [Homo sapiens]
histone H2A.V isoform 4 [Homo sapiens]
gi|41406069|ref|NP_958924.1|

Protein
RecName: Full=Synaptotagmin-13; AltName: Full=Synaptotagmin XIII; Short=SytXIII
RecName: Full=Synaptotagmin-13; AltName: Full=Synaptotagmin XIII; Short=SytXIII
gi|74749900|sp|Q7L8C5.1|SYT13_HUMAN

Protein
LOC109280000 [Mus musculus]
LOC109280000 [Mus musculus]
Gene ID:109280000

Gene
LOC125681432 [Ostrea edulis]
LOC125681432 [Ostrea edulis]
Gene ID:125681432

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000484797	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]
SCV000606238	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000967745	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 27, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19026292, 30586733, 32143996, 27765764, 25741868
SCV004820220	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15199436, 15321837, 19026292, 20809525, 27765764, 28645073, 30586733, 32143996, 33740630, 25741868

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	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.

Austin MA, Hutter CM, Zimmern RL, Humphries SE.

Am J Epidemiol. 2004 Sep 1;160(5):407-20. Review.

PubMed [citation]

PMID:: 15321837

See all PubMed Citations (10)

Details of each submission

From Robarts Research Institute, Western University, SCV000484797.1

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606238.1

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

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967745.3

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

Description

The p.Thr274HisfsX96 variant in LDLR has been reported in at least 6 individuals with familial hypercholesterolemia (FH), 2 of whom were suspected to have homozygous FH but an LDLR variant affecting the other copy was not identified (Kolansky 2008 PMID: 19026292, Wang 2016 PMID: 27765764, Gidding 2020 PMID: 232143996). It was also reported in 1 individual with an early-onset myocardial infarction (Khera 2019 PMID: 30586733) and by other clinical laboratories in ClinVar (Variation ID 369863). Additionally, it has been identified in 0.002% (2/129158) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies measuring LDL receptor activity in cultured skin fibroblasts show that this variant results in significantly reduced receptor activity (<2%, Kolansky 2008 PMID: 19026292). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 274 and leads to a premature termination codon 96 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PS3_Supporting.

#	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, SCV004820220.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

The c.820del (p.Thr274Hisfs*96) variant of the LDLR gene introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in heterozygous status in at least five individuals who fulfill the clinical criteria of familial hypercholesterolemia (FH) (PMID: 27765764, 32143996), and in 1/2081 individual from an early-onset myocardial infarction cohort while absent in 3761 controls (PMID: 30586733). This variant in homozygous status has been detected in two individuals with severe FH (>500mg/dL) and in-vitro functional studies using patients derived skin fibroblasts showed significantly reduced LDLR (<2%) activity (PMID: 19026292). Loss-of-function variants in LDLR are well known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 15199436? 9698020, 16389549, 17765246, 17935672, 33740630) and by several ClinVar submitters (ClinVar ID: 251478, 251475). This variant is found to be rare (2/282836; 0.000007) in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in the ClinVar (ClinVar ID: 369863). Therefore, the c.820del (p.Thr274Hisfs*96) variant in the LDLR gene is classified as pathogenic.

#	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: Nov 3, 2024

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