NM_000527.5(LDLR):c.1351A>G (p.Ile451Val) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (1 submission)
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:: RCV003388673.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1351A>G (p.Ile451Val)]

NM_000527.5(LDLR):c.1351A>G (p.Ile451Val)

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.1351A>G (p.Ile451Val)

HGVS:

NC_000019.10:g.11113442A>G
NG_009060.1:g.29062A>G
NM_000527.5:c.1351A>GMANE SELECT
NM_001195798.2:c.1351A>G
NM_001195799.2:c.1228A>G
NM_001195800.2:c.847A>G
NM_001195803.2:c.970A>G
NP_000518.1:p.Ile451Val
NP_000518.1:p.Ile451Val
NP_001182727.1:p.Ile451Val
NP_001182728.1:p.Ile410Val
NP_001182729.1:p.Ile283Val
NP_001182732.1:p.Ile324Val
LRG_274t1:c.1351A>G
LRG_274:g.29062A>G
LRG_274p1:p.Ile451Val
NC_000019.9:g.11224118A>G
NM_000527.4:c.1351A>G

Protein change:

I283V

Molecular consequence:

NM_000527.5:c.1351A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1351A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1228A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.847A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.970A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004100381	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	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

SCV004100381

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Neuberg Centre For Genomic Medicine, NCGM, SCV004100381.1

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

Description

The missense variant p.I451V in LDLR (NM_000527.5) has not been reported previously in affected individuals. Other variations affecting the same amino acid residue Ile451Thr, Ile451Phe has been submitted to UMD database (as Ile430Thr and Ile430Phe) as well as ClinVar database as Likely Pathogenic. The Ile430Thr was present in heterozygous state and segregated within the affected individuals in a Greek family (Manoli P et al).The p.I451V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico predictions are contradictory (SIFT-tolerated, Polyphen-2 -Damaging) and the residue is conserved across species. For these reasons, this variant has been classified as Uncertain Significance- Likely Damaging type.

#	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

Last Updated: Apr 6, 2024

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