NM_000527.5(LDLR):c.226G>T (p.Gly76Trp) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 23, 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:: RCV002446472.2

Allele description [Variation Report for NM_000527.5(LDLR):c.226G>T (p.Gly76Trp)]

NM_000527.5(LDLR):c.226G>T (p.Gly76Trp)

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.226G>T (p.Gly76Trp)

Other names:

NM_000527.5(LDLR):c.226G>T

HGVS:

NC_000019.10:g.11102699G>T
NG_009060.1:g.18319G>T
NM_000527.5:c.226G>TMANE SELECT
NM_001195798.2:c.226G>T
NM_001195799.2:c.190+2354G>T
NM_001195800.2:c.226G>T
NM_001195803.2:c.226G>T
NP_000518.1:p.Gly76Trp
NP_000518.1:p.Gly76Trp
NP_001182727.1:p.Gly76Trp
NP_001182729.1:p.Gly76Trp
NP_001182732.1:p.Gly76Trp
LRG_274t1:c.226G>T
LRG_274:g.18319G>T
NC_000019.9:g.11213375G>T
NM_000527.4(LDLR):c.226G>T
NM_000527.4:c.226G>T
c.226G>T

Protein change:

G76W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000035; dbSNP: rs574337291

NCBI 1000 Genomes Browser:

rs574337291

Molecular consequence:

NM_001195799.2:c.190+2354G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.226G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002734015	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 23, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17765246, 25741862, 32719484 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002734015

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 23, 2021)

germline

clinical testing

PubMed (3)
[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

Familial hypercholesterolaemia in Portugal.

Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK; Investigators of Portuguese FH Study..

Atherosclerosis. 2008 Feb;196(2):633-42. Epub 2007 Aug 31.

PubMed [citation]

PMID:: 17765246

The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia.

Benito-Vicente A, Alves AC, Etxebarria A, Medeiros AM, Martin C, Bourbon M.

Genet Med. 2015 Dec;17(12):980-8. doi: 10.1038/gim.2015.14. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741862

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002734015.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.G76W variant (also known as c.226G>T), located in coding exon 3 of the LDLR gene, results from a G to T substitution at nucleotide position 226. The glycine at codon 76 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort with limited clinical details and in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). An in vitro assay showed this alteration may not impact protein function (Benito-Vicente A et al. Genet Med, 2015 Dec;17:980-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration 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: Sep 29, 2024

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