NM_000527.5(LDLR):c.680_682delinsCGGTATGGACTGCA (p.Asp227fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 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:: RCV000484687.7

Allele description [Variation Report for NM_000527.5(LDLR):c.680_682delinsCGGTATGGACTGCA (p.Asp227fs)]

NM_000527.5(LDLR):c.680_682delinsCGGTATGGACTGCA (p.Asp227fs)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.680_682delinsCGGTATGGACTGCA (p.Asp227fs)

HGVS:

NC_000019.10:g.11105586_11105588delinsCGGTATGGACTGCA
NG_009060.1:g.21206_21208delinsCGGTATGGACTGCA
NM_000527.5:c.680_682delinsCGGTATGGACTGCAMANE SELECT
NM_001195798.2:c.680_682delinsCGGTATGGACTGCA
NM_001195799.2:c.557_559delinsCGGTATGGACTGCA
NM_001195800.2:c.314-1806_314-1804delinsCGGTATGGACTGCA
NM_001195803.2:c.314-979_314-977delinsCGGTATGGACTGCA
NP_000518.1:p.Asp227fs
NP_000518.1:p.Asp227fs
NP_001182727.1:p.Asp227fs
NP_001182728.1:p.Asp186fs
LRG_274t1:c.680_682delinsCGGTATGGACTGCA
LRG_274:g.21206_21208delinsCGGTATGGACTGCA
LRG_274p1:p.Asp227fs
NC_000019.9:g.11216262_11216264delinsCGGTATGGACTGCA
NM_000527.4:c.680_682delACGinsCGGTATGGACTGCA
NM_000527.4:c.680_682delinsCGGTATGGACTGCA

Protein change:

D186fs

Links:

dbSNP: rs879254637

NCBI 1000 Genomes Browser:

rs879254637

Molecular consequence:

NM_000527.5:c.680_682delinsCGGTATGGACTGCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.680_682delinsCGGTATGGACTGCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.557_559delinsCGGTATGGACTGCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.314-1806_314-1804delinsCGGTATGGACTGCA - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-979_314-977delinsCGGTATGGACTGCA - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000572556	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 29, 2023)	germline	clinical testing	Citation Link,
SCV004219995	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 7, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29572815, 26802169, 17539906, 28161202, 32770674, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000572556

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Apr 29, 2023)

germline

clinical testing

Citation Link,

SCV004219995

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Jun 7, 2023)

unknown

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Single, short in-del, and copy number variations detection in monogenic dyslipidemia using a next-generation sequencing strategy.

Marmontel O, Charrière S, Simonet T, Bonnet V, Dumont S, Mahl M, Jacobs C, Nony S, Chabane K, Bozon D, Janin A, Peretti N, Lachaux A, Bardel C, Millat G, Moulin P, Marçais C, Di Filippo M.

Clin Genet. 2018 Jul;94(1):132-140. doi: 10.1111/cge.13250. Epub 2018 Apr 25.

PubMed [citation]

PMID:: 29572815

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

Wintjens R, Bozon D, Belabbas K, MBou F, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M, et al.

J Lipid Res. 2016 Mar;57(3):482-91. doi: 10.1194/jlr.P055699. Epub 2016 Jan 22.

PubMed [citation]

PMID:: 26802169
PMCID:: PMC4766997

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000572556.8

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

Description

Very similar insertion/deletion (c.679del4ins15; originally reported as 676insACGGTATGGACTGCAdelGACG), has been identified in one individual with primary hypercholesterolemia in the published literature (Nauck et al., 2001); Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.Asp207AlafsX; This variant is associated with the following publications: (PMID: 17539906, 31447099, 28161202, 32770674, 11462246, 27535533)

#	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, SCV004219995.1

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

Description

The LDLR c.680_682delins14 (p.Asp227Alafs*42) variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature in individuals with definite or suspected familial hypercholesterolemia (PMIDs: 17539906 (2007), 26802169 (2016), 28161202 (2017), 29572815 (2018), and 32770674 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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

Last Updated: Sep 1, 2024

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