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

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Feb 16, 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:: RCV000791393.14

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]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544653	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 16, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20809525, 28645073, 12417285, 20045108, 20538126, 21376320, 23375686, 28492532
SCV001356940	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 14, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001361871	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 29, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16314194, 12417285, 19026292, 20045108, 20538126, 28965616 Citation Link,
SCV002086866	Natera, Inc.	no assertion criteria provided	Pathogenic (Jun 18, 2021)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene.

Jiang L, Benito-Vicente A, Tang L, Etxebarria A, Cui W, Uribe KB, Pan XD, Ostolaza H, Yang SW, Zhou YJ, Martin C, Wang LY.

Atherosclerosis. 2017 Aug;263:163-170. doi: 10.1016/j.atherosclerosis.2017.06.014. Epub 2017 Jun 8.

PubMed [citation]

PMID:: 28645073

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544653.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Gln739*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 12417285, 20045108, 20538126, 21376320, 23375686). This variant is also known as p.Gln718X. ClinVar contains an entry for this variant (Variation ID: 252258). For these reasons, this variant has been classified as Pathogenic.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001356940.2

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

Description

This variant (also known as Q718X) changes 1 nucleotide in exon 15 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID:12417285, 20045108, 20538126, 21376320, 23375686). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361871.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: LDLR c.2215C>T (p.Gln739X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251316 control chromosomes (gnomAD). c.2215C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Yu_2002, Robles-Osorio_2006, Romano_2010, Chiou_2010, Pirillo_2017, Kolansky_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reported that the variant resulted in less than 2% of normal LDLR activity in patient derived skin fibroblasts (Kolansky_2008). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and as VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 Natera, Inc., SCV002086866.1

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

Last Updated: Sep 29, 2024

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