NM_000527.5(LDLR):c.1586G>A (p.Gly529Asp) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 16, 2021
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:: RCV001376907.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1586G>A (p.Gly529Asp)]

NM_000527.5(LDLR):c.1586G>A (p.Gly529Asp)

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.1586G>A (p.Gly529Asp)

HGVS:

NC_000019.10:g.11113762G>A
NG_009060.1:g.29382G>A
NM_000527.5:c.1586G>AMANE SELECT
NM_001195798.2:c.1586G>A
NM_001195799.2:c.1463G>A
NM_001195800.2:c.1082G>A
NM_001195803.2:c.1205G>A
NP_000518.1:p.Gly529Asp
NP_000518.1:p.Gly529Asp
NP_001182727.1:p.Gly529Asp
NP_001182728.1:p.Gly488Asp
NP_001182729.1:p.Gly361Asp
NP_001182732.1:p.Gly402Asp
LRG_274t1:c.1586G>A
LRG_274:g.29382G>A
NC_000019.9:g.11224438G>A
NM_000527.4(LDLR):c.1586G>A
NM_000527.4:c.1586G>A
c.1586G>A
p.Gly529Asp

Protein change:

G361D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001464; dbSNP: rs878854025

NCBI 1000 Genomes Browser:

rs878854025

Molecular consequence:

NM_000527.5:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1082G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1205G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV001574101	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 16, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17576681, 9536098, 21722902, 22998978, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574101

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 16, 2021)

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 Invitae, SCV001574101.4

#	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. Nucleotide substitutions within 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 21722902, 22998978). ClinVar contains an entry for this variant (Variation ID: 237863). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 529 of the LDLR protein (p.Gly529Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant also falls at the last nucleotide of exon 10, 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: May 19, 2024

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