NM_000527.5(LDLR):c.1026C>G (p.Asp342Glu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 11, 2022
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:: RCV000590555.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1026C>G (p.Asp342Glu)]

NM_000527.5(LDLR):c.1026C>G (p.Asp342Glu)

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.1026C>G (p.Asp342Glu)

Other names:

FH New York-1

HGVS:

NC_000019.10:g.11110737C>G
NG_009060.1:g.26357C>G
NM_000527.5:c.1026C>GMANE SELECT
NM_001195798.2:c.1026C>G
NM_001195799.2:c.903C>G
NM_001195800.2:c.522C>G
NM_001195803.2:c.645C>G
NP_000518.1:p.Asp342Glu
NP_000518.1:p.Asp342Glu
NP_001182727.1:p.Asp342Glu
NP_001182728.1:p.Asp301Glu
NP_001182729.1:p.Asp174Glu
NP_001182732.1:p.Asp215Glu
LRG_274t1:c.1026C>G
LRG_274:g.26357C>G
LRG_274p1:p.Asp342Glu
NC_000019.9:g.11221413C>G
NM_000527.4:c.1026C>G
P01130:p.Asp342Glu
c.1026C>G

Protein change:

D174E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001327; UniProtKB: P01130#VAR_005365; dbSNP: rs780563386

NCBI 1000 Genomes Browser:

rs780563386

Molecular consequence:

NM_000527.5:c.1026C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1026C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.903C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.522C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.645C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000520996	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 11, 2022)	germline	clinical testing	Citation Link,
SCV000697180	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 21, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18607183, 8599353, 18325082, 11435110 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000520996

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 11, 2022)

germline

clinical testing

Citation Link,

SCV000697180

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 21, 2016)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

What is the clinical utility of DNA testing in patients with familial hypercholesterolaemia?

Humphries SE, Norbury G, Leigh S, Hadfield SG, Nair D.

Curr Opin Lipidol. 2008 Aug;19(4):362-8. doi: 10.1097/MOL.0b013e32830636e5. Review.

PubMed [citation]

PMID:: 18607183

FH Tulsa-1 and -2: two unique alleles for familial hypercholesterolemia presenting in an affected two-year-old African-American male.

Blackett PR, Altmiller DH, Jelley D, Wilson DP.

Am J Med Genet. 1995 Nov 20;59(3):300-3.

PubMed [citation]

PMID:: 8599353

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000520996.7

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

Description

Identified in a patient with FH who also harbored another variant in trans in the LDLR gene in published literature (Hobbs et al., 1992); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as D321E and FH New York-1; This variant is associated with the following publications: (PMID: 31401775, 18325082, 1301956)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697180.1

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

Description

Variant summary: The c.1026C>G (p.Asp342Glu) in LDLR gene is a missense change that involves a non-conserved nucleotide and 4/4 in silico tools predict benign outcome. The variant of interest is located within EGF-like functional domain, although the functional impact of this missense change is yet to be studied. The variant is absent from the large control population dataset of ExAC but has been reported in compound heterozygosity with a likely pathogenic variant in affected individual via published reports (Hobbs, 1992). In addition, it was cited as Likely Benign by a reputable database/clinical laboratory and published report (Leigh, 2008). At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.

#	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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