NM_000527.5(LDLR):c.940G>A (p.Gly314Arg) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 9, 2024
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:: RCV002372047.3

Allele description [Variation Report for NM_000527.5(LDLR):c.940G>A (p.Gly314Arg)]

NM_000527.5(LDLR):c.940G>A (p.Gly314Arg)

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.940G>A (p.Gly314Arg)

HGVS:

NC_000019.10:g.11107514G>A
NG_009060.1:g.23134G>A
NM_000527.5:c.940G>AMANE SELECT
NM_001195798.2:c.940G>A
NM_001195799.2:c.817G>A
NM_001195800.2:c.436G>A
NM_001195803.2:c.559G>A
NP_000518.1:p.Gly314Arg
NP_000518.1:p.Gly314Arg
NP_001182727.1:p.Gly314Arg
NP_001182728.1:p.Gly273Arg
NP_001182729.1:p.Gly146Arg
NP_001182732.1:p.Gly187Arg
LRG_274t1:c.940G>A
LRG_274:g.23134G>A
LRG_274p1:p.Gly314Arg
NC_000019.9:g.11218190G>A
NM_000527.4:c.940G>A
c.940G>A

Protein change:

G146R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000695; dbSNP: rs72658858

NCBI 1000 Genomes Browser:

rs72658858

Molecular consequence:

NM_000527.5:c.940G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.940G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.817G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.436G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002685014	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 9, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17347910, 22881376, 22995991, 25647241, 26332594, 28104544, 28349888, 30778614, 33794673, 35047021 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002685014

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 9, 2024)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

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

Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations.

Widhalm K, Dirisamer A, Lindemayr A, Kostner G.

J Inherit Metab Dis. 2007 Apr;30(2):239-47. Epub 2007 Mar 8.

PubMed [citation]

PMID:: 17347910

Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment.

Usifo E, Leigh SE, Whittall RA, Lench N, Taylor A, Yeats C, Orengo CA, Martin AC, Celli J, Humphries SE.

Ann Hum Genet. 2012 Sep;76(5):387-401. doi: 10.1111/j.1469-1809.2012.00724.x.

PubMed [citation]

PMID:: 22881376

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002685014.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The p.G314R variant (also known as c.940G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 940. The glycine at codon 314 is replaced by arginine, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 6 and may have some effect on normal mRNA splicing. This variant (also described as legacy p.G293R) has been reported in hypercholesterolemia cohorts; however, clinical details were limited in many cases (Widhalm K et al. J Inherit Metab Dis, 2007 Apr;30:239-47; Durst R et al. Atherosclerosis, 2017 02;257:55-63; Futema M et al. Atherosclerosis, 2017 05;260:47-55; Turkyilmaz A et al. Metab Syndr Relat Disord, 2021 08;19:340-346). Limited functional analyses suggested no significant impact (Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

#	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: Feb 25, 2025

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