NM_000527.5(LDLR):c.118A>G (p.Ile40Val) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 28, 2023
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:: RCV000509299.4

Allele description [Variation Report for NM_000527.5(LDLR):c.118A>G (p.Ile40Val)]

NM_000527.5(LDLR):c.118A>G (p.Ile40Val)

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.118A>G (p.Ile40Val)

HGVS:

NC_000019.10:g.11100273A>G
NG_009060.1:g.15893A>G
NM_000527.5:c.118A>GMANE SELECT
NM_001195798.2:c.118A>G
NM_001195799.2:c.118A>G
NM_001195800.2:c.118A>G
NM_001195803.2:c.118A>G
NP_000518.1:p.Ile40Val
NP_000518.1:p.Ile40Val
NP_001182727.1:p.Ile40Val
NP_001182728.1:p.Ile40Val
NP_001182729.1:p.Ile40Val
NP_001182732.1:p.Ile40Val
LRG_274t1:c.118A>G
LRG_274:g.15893A>G
LRG_274p1:p.Ile40Val
NC_000019.9:g.11210949A>G
NM_000527.4:c.118A>G

Protein change:

I40V

Links:

dbSNP: rs765969972

NCBI 1000 Genomes Browser:

rs765969972

Molecular consequence:

NM_000527.5:c.118A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.118A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.118A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.118A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.118A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

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SGCZ protein [Homo sapiens]
SGCZ protein [Homo sapiens]
gi|115528889|gb|AAI25038.1|

Protein
RecName: Full=Protein arginine N-methyltransferase 9; AltName: Full=Protein argi...
RecName: Full=Protein arginine N-methyltransferase 9; AltName: Full=Protein arginine N-methyltransferase 10
gi|74758248|sp|Q6P2P2.1|ANM9_HUMAN

Protein
RecName: Full=Cytohesin-3; AltName: Full=ARF nucleotide-binding site opener 3; S...
RecName: Full=Cytohesin-3; AltName: Full=ARF nucleotide-binding site opener 3; Short=Protein ARNO3; AltName: Full=General receptor of phosphoinositides 1; Short=Grp1; AltName: Full=PH, SEC7 and coiled-coil domain-containing protein 3
gi|13124042|sp|O43739.2|CYH3_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000607419	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002793805	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 5, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820117	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 28, 2023)	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

SCV000607419

Fundacion Hipercolesterolemia Familiar - SAFEHEART

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 1, 2016)

germline

research

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

SCV002793805

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 5, 2021)

unknown

clinical testing

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

SCV004820117

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 28, 2023)

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	2	not provided	not provided	108544	not provided	clinical testing, research
not provided	unknown	unknown	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607419.1

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

Description

%MAF(ExAC):0.0008258

#	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 Fulgent Genetics, Fulgent Genetics, SCV002793805.1

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

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

From All of Us Research Program, National Institutes of Health, SCV004820117.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant (also known as p.Ile19Val in the mature protein) replaces isoleucine with valine at codon 40 of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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