NM_000527.5(LDLR):c.2043C>A (p.Cys681Ter) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Apr 8, 2024
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:: RCV000481771.10

Allele description [Variation Report for NM_000527.5(LDLR):c.2043C>A (p.Cys681Ter)]

NM_000527.5(LDLR):c.2043C>A (p.Cys681Ter)

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.2043C>A (p.Cys681Ter)

Other names:

C660*; FH Lebanese; NP_000518.1:p.C681*

HGVS:

NC_000019.10:g.11120425C>A
NG_009060.1:g.36045C>A
NM_000527.5:c.2043C>AMANE SELECT
NM_001195798.2:c.2043C>A
NM_001195799.2:c.1920C>A
NM_001195800.2:c.1539C>A
NM_001195803.2:c.1606+192C>A
NP_000518.1:p.Cys681Ter
NP_000518.1:p.Cys681Ter
NP_001182727.1:p.Cys681Ter
NP_001182728.1:p.Cys640Ter
NP_001182729.1:p.Cys513Ter
LRG_274t1:c.2043C>A
LRG_274:g.36045C>A
LRG_274p1:p.Cys681Ter
NC_000019.9:g.11231101C>A
NM_000527.4:c.2043C>A
c.2043C>A
p.Cys681*
p.Cys681X

Protein change:

C513*; CYS660TER

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001592; OMIM: 606945.0016

Molecular consequence:

NM_001195803.2:c.1606+192C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2043C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.2043C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.1920C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.1539C>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Rattus norvegicus stimulator of interferon response cGAMP interactor ...
PREDICTED: Rattus norvegicus stimulator of interferon response cGAMP interactor 1 (Sting1), transcript variant X1, mRNA
gi|1958743572|ref|XM_039097039.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568525	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 8, 2024)	germline	clinical testing	Citation Link,
SCV000809473	Gharavi Laboratory, Columbia University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001134256	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Mar 6, 2023)	unknown	clinical testing	PubMed (22) [See all records that cite these PMIDs] 19319977, 21145767, 11668627, 25461735, 3025214, 9664576, 14974088, 28873201, 22487947, 31578082, 25487149, 25525159, 30179711, 31447099, 32231684, 32770674, 33303402, 33418990, 33740630, 34037665, 34040191, 26467025
SCV004227682	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 4, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19319977, 22487947, 28873201, 3025214, 31578082, 34029164, 34321884, 25741868
SCV005198662	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Homozygous familial hypercholesterolemia in Lebanon: a genotype/phenotype correlation.

Fahed AC, Safa RM, Haddad FF, Bitar FF, Andary RR, Arabi MT, Azar ST, Nemer G.

Mol Genet Metab. 2011 Feb;102(2):181-8. doi: 10.1016/j.ymgme.2010.11.006. Epub 2010 Nov 11.

PubMed [citation]

PMID:: 21145767

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent.

Wang J, Huff E, Janecka L, Hegele RA.

Hum Mutat. 2001 Oct;18(4):359.

PubMed [citation]

PMID:: 11668627

See all PubMed Citations (25)

Details of each submission

From GeneDx, SCV000568525.7

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

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Reported many times in the heterozygous, compound heterozygous, and homozygous states in individuals with FH (PMID: 9664576, 9259195, 3025214, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711); Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (PMID: 19319977); Published functional studies suggest a damaging effect on protein expression and binding (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C660X); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711, 29407885, 34040191, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 35379577, 32009526, 33955087, 34321884, 15321837, 19319977, 37128917, 31578082)

#	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 Gharavi Laboratory, Columbia University, SCV000809473.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134256.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (22)

Description

This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a Lebanese founder mutation, but has also been identified in multiple other ethnic groups, in individuals and families with familial hypercholesterolemia (PMID: 28873201 (2017), 25461735 (2015), 22487947 (2012), 21145767 (2011), 19319977 (2009), 14974088 (2004), 11668627 (2001), 9664576 (1998), 3025214 (1987)). In a functional study, this variant was found to have a damaging effect on LDLR expression and binding (PMID: 31578082 (2019)). Based on the available information, this variant is classified as pathogenic.

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004227682.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (8)

Description

PP1, PS3, PS4_moderate, PVS1

#	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		2	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198662.1

#	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

Last Updated: Nov 3, 2024

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