NM_000527.5(LDLR):c.1845G>A (p.Glu615=) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 22, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001034634.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1845G>A (p.Glu615=)]

NM_000527.5(LDLR):c.1845G>A (p.Glu615=)

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.1845G>A (p.Glu615=)

Other names:

NM_000527.5(LDLR):c.1845G>A; p.Glu615=

HGVS:

NC_000019.10:g.11116998G>A
NG_009060.1:g.32618G>A
NM_000527.5:c.1845G>AMANE SELECT
NM_001195798.2:c.1845G>A
NM_001195799.2:c.1722G>A
NM_001195800.2:c.1341G>A
NM_001195803.2:c.1464G>A
NP_000518.1:p.Glu615=
NP_000518.1:p.Glu615=
NP_001182727.1:p.Glu615=
NP_001182728.1:p.Glu574=
NP_001182729.1:p.Glu447=
NP_001182732.1:p.Glu488=
LRG_274t1:c.1845G>A
LRG_274:g.32618G>A
LRG_274p1:p.Glu615=
NC_000019.9:g.11227674G>A
NM_000527.4:c.1845G>A
c.1845G>A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000612; dbSNP: rs879255047

NCBI 1000 Genomes Browser:

rs879255047

Molecular consequence:

NM_000527.5:c.1845G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.1845G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.1722G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195800.2:c.1341G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195803.2:c.1464G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

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

Recent activity

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Eurynassa servillei isolate column11_B141 NADH dehydrogenase subunit 2 (ND2) gen...
Eurynassa servillei isolate column11_B141 NADH dehydrogenase subunit 2 (ND2) gene, partial cds; mitochondrial
gi|2772184584|gb|OR579787.1|

Nucleotide
OMIM Links for GEO Profiles (Select 55745134) (2)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752417	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17539906, 17576681, 9536098, 28492532
SCV001355016	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752417

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 22, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001355016

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 1, 2018)

germline

clinical testing

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

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

Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia.

Taylor A, Tabrah S, Wang D, Sozen M, Duxbury N, Whittall R, Humphries SE, Norbury G.

Clin Genet. 2007 Jun;71(6):561-8.

PubMed [citation]

PMID:: 17539906

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752417.6

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

Description

This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change affects codon 615 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 17539906; Invitae). For these reasons, this variant has been classified as 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 disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 252065). This variant is also known as IVS13-2G>A.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001355016.2

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

Description

Variant of Uncertain Significance due to insufficient evidence: This synonymous variant does not change the amino acid sequence of the LDLR protein. This variant changes the conserved, last nucleotide of exon 12. Computational splicing tools suggest that this variant may adversely impact RNA splicing. To our knowledge, RNA assays have not been performed to investigate this prediction. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 17539906). This variant is rare in the general population and has been identified in 1/30958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

#	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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