NM_000527.5(LDLR):c.1060G>A (p.Asp354Asn) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 3, 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:: RCV003074993.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1060G>A (p.Asp354Asn)]

NM_000527.5(LDLR):c.1060G>A (p.Asp354Asn)

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.1060G>A (p.Asp354Asn)

HGVS:

NC_000019.10:g.11110771G>A
NG_009060.1:g.26391G>A
NM_000527.5:c.1060G>AMANE SELECT
NM_001195798.2:c.1060G>A
NM_001195799.2:c.937G>A
NM_001195800.2:c.556G>A
NM_001195803.2:c.679G>A
NP_000518.1:p.Asp354Asn
NP_000518.1:p.Asp354Asn
NP_001182727.1:p.Asp354Asn
NP_001182728.1:p.Asp313Asn
NP_001182729.1:p.Asp186Asn
NP_001182732.1:p.Asp227Asn
LRG_274t1:c.1060G>A
LRG_274:g.26391G>A
LRG_274p1:p.Asp354Asn
NC_000019.9:g.11221447G>A
NM_000527.4:c.1060G>A

Protein change:

D186N

Molecular consequence:

NM_000527.5:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.937G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.556G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.679G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Homo sapiens actin related protein 1B (ACTR1B), mRNA
Homo sapiens actin related protein 1B (ACTR1B), mRNA
gi|1653960423|ref|NM_005735.4|

Nucleotide
Homo sapiens mRNA; cDNA DKFZp686J1719 (from clone DKFZp686J1719)
Homo sapiens mRNA; cDNA DKFZp686J1719 (from clone DKFZp686J1719)
gi|21733049|emb|AL832481.1|

Nucleotide
Homo sapiens cDNA FLJ30135 fis, clone BRACE2000061
Homo sapiens cDNA FLJ30135 fis, clone BRACE2000061
gi|16549295|dbj|AK054697.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003461827	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 3, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17576681, 9536098, 29353225, 32331935, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003461827

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 3, 2022)

germline

clinical testing

PubMed (5)
[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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003461827.2

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 29353225, 32331935; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 354 of the LDLR protein (p.Asp354Asn). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon.

#	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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