NM_000527.5(LDLR):c.2215C>T (p.Gln739Ter) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Aug 29, 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:: RCV000237494.10

Allele description [Variation Report for NM_000527.5(LDLR):c.2215C>T (p.Gln739Ter)]

NM_000527.5(LDLR):c.2215C>T (p.Gln739Ter)

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.2215C>T (p.Gln739Ter)

Other names:

NP_000518.1:p.Q739*; NM_000527.5(LDLR):c.2215C>T; p.Gln739Ter

HGVS:

NC_000019.10:g.11123248C>T
NG_009060.1:g.38868C>T
NM_000527.5:c.2215C>TMANE SELECT
NM_001195798.2:c.2215C>T
NM_001195799.2:c.2092C>T
NM_001195800.2:c.1711C>T
NM_001195803.2:c.1681C>T
NP_000518.1:p.Gln739Ter
NP_000518.1:p.Gln739Ter
NP_001182727.1:p.Gln739Ter
NP_001182728.1:p.Gln698Ter
NP_001182729.1:p.Gln571Ter
NP_001182732.1:p.Gln561Ter
LRG_274t1:c.2215C>T
LRG_274:g.38868C>T
LRG_274p1:p.Gln739Ter
NC_000019.9:g.11233924C>T
NM_000527.4:c.2215C>T
c.2215C>T
p.(Gln739*)
p.Gln739*

Protein change:

Q561*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000289; dbSNP: rs370018159

NCBI 1000 Genomes Browser:

rs370018159

Molecular consequence:

NM_000527.5:c.2215C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.2215C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.2092C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.1711C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.1681C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000295919	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 12417285, 20538126, 23375686 Citation Link,
SCV000484732	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]
SCV000503474	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)	Uncertain significance (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432561	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 4, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001653657	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12417285, 25525159, 28965616, 31491741, 32041611, 32331935, 25741868
SCV002817128	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Aug 29, 2022)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	8	not provided	not provided	2605	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia.

Chiou KR, Charng MJ.

Am J Cardiol. 2010 Jun 15;105(12):1752-8. doi: 10.1016/j.amjcard.2010.01.356. Epub 2010 May 4.

PubMed [citation]

PMID:: 20538126

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (11)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295919.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (3)
2	not provided	1	not provided	not provided	literature only	PubMed (3)
3	not provided	1	not provided	not provided	literature only	PubMed (3)

#	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
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Robarts Research Institute, Western University, SCV000484732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	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, SCV000503474.1

#	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/FH-Japan

#	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, SCV001432561.1

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

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653657.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (7)

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002817128.1

#	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.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PM2 and 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PVS1 - Stop in codon 739. It is upstream of amino acid 830. PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Robarts Research Institute after alternative causes of high cholesterol were excluded.

#	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: Sep 29, 2024

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