NM_000527.4(LDLR):c.664_681dup18 (p.Asp227_Glu228insCysLysAspLysSerAsp) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 10, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001201377.11

Allele description [Variation Report for NM_000527.4(LDLR):c.664_681dup18 (p.Asp227_Glu228insCysLysAspLysSerAsp)]

NM_000527.4(LDLR):c.664_681dup18 (p.Asp227_Glu228insCysLysAspLysSerAsp)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.4(LDLR):c.664_681dup18 (p.Asp227_Glu228insCysLysAspLysSerAsp)

Other names:

FH Padua-4

HGVS:

NC_000019.10:g.11105570_11105587dup
NG_009060.1:g.21190_21207dup
NM_000527.5:c.664_681dupMANE SELECT
NM_001195798.2:c.664_681dup
NM_001195799.2:c.541_558dup
NM_001195800.2:c.314-1822_314-1805dup
NM_001195803.2:c.314-995_314-978dup
NP_000518.1:p.Cys222_Asp227dup
NP_001182727.1:p.Cys222_Asp227dup
NP_001182728.1:p.Cys181_Asp186dup
LRG_274:g.21190_21207dup
NC_000019.10:g.11105587_11105588insTGCAAGGACAAATCTGAC
NC_000019.9:g.11216242_11216243insGACTGCAAGGACAAATCT
NC_000019.9:g.11216246_11216263dup
NM_000527.4:c.664_681dup18
c.664_681dup
p.(Cys222_Asp227dup)

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000097; OMIM: 606945.0051; dbSNP: rs387906306

NCBI 1000 Genomes Browser:

rs387906306

Molecular consequence:

NM_000527.5:c.664_681dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001195798.2:c.664_681dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001195799.2:c.541_558dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001195800.2:c.314-1822_314-1805dup - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-995_314-978dup - 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
SCV000285033	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 10, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7581403, 7649546, 10978268, 20145306, 28492532
SCV002086379	Natera, Inc.	no assertion criteria provided	Pathogenic (May 7, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000285033

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 10, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002086379

Natera, Inc.

no assertion criteria provided

Pathogenic
(May 7, 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

A de novo duplication in the low density lipoprotein receptor gene.

Kotze MJ, Theart L, Peeters A, Langenhoven E.

Hum Mutat. 1995;6(2):181-3. No abstract available.

PubMed [citation]

PMID:: 7581403

Screening for mutations in exon 4 of the LDL receptor gene in a German population with severe hypercholesterolemia.

Giesel J, Holzem G, Oette K.

Hum Genet. 1995 Sep;96(3):301-4.

PubMed [citation]

PMID:: 7649546

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000285033.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3733). This variant is also known as p.201-206dup and CKDKSD206‚Äì207ins. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 7581403, 7649546, 10978268, 20145306). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs387906306, gnomAD 0.0009%). This variant, c.664_681dup, results in the insertion of 6 amino acid(s) of the LDLR protein (p.Cys222_Asp227dup), but otherwise preserves the integrity of the reading frame.

#	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., SCV002086379.1

#	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: Oct 8, 2024

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