NM_000527.5(LDLR):c.680_682delinsCA (p.Asp227fs) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 13, 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:: RCV001181306.7

Allele description [Variation Report for NM_000527.5(LDLR):c.680_682delinsCA (p.Asp227fs)]

NM_000527.5(LDLR):c.680_682delinsCA (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_682delinsCA (p.Asp227fs)

HGVS:

NC_000019.10:g.11105586_11105588delinsCA
NG_009060.1:g.21206_21208delinsCA
NM_000527.5:c.680_682delinsCAMANE SELECT
NM_001195798.2:c.680_682delinsCA
NM_001195799.2:c.557_559delinsCA
NM_001195800.2:c.314-1806_314-1804delinsCA
NM_001195803.2:c.314-979_314-977delinsCA
NP_000518.1:p.Asp227fs
NP_001182727.1:p.Asp227fs
NP_001182728.1:p.Asp186fs
LRG_274:g.21206_21208delinsCA
NC_000019.9:g.11216262_11216264delinsCA

Protein change:

D186fs

Links:

dbSNP: rs879254637

NCBI 1000 Genomes Browser:

rs879254637

Molecular consequence:

NM_000527.5:c.680_682delinsCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195798.2:c.680_682delinsCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195799.2:c.557_559delinsCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195800.2:c.314-1806_314-1804delinsCA - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-979_314-977delinsCA - intron variant - [Sequence Ontology: SO:0001627]

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
SCV001346422	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 25, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001419821	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20809525, 28645073, 26802169, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001346422

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 25, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001419821

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 13, 2023)

germline

clinical testing

PubMed (4)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001346422.2

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

Description

This variant replaces three nucleotides in exon 4 of the LDLR gene with two new nucleotides, creating a frameshift and 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 a French individual affected with hypercholesterolemia (PMID: 26802169). 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001419821.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Asp227Alafs*38) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 26802169). 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

Last Updated: Sep 29, 2024

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