NM_000527.5(LDLR):c.1580T>C (p.Val527Ala) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV002478493.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1580T>C (p.Val527Ala)]

NM_000527.5(LDLR):c.1580T>C (p.Val527Ala)

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.1580T>C (p.Val527Ala)

HGVS:

NC_000019.10:g.11113756T>C
NG_009060.1:g.29376T>C
NM_000527.5:c.1580T>CMANE SELECT
NM_001195798.2:c.1580T>C
NM_001195799.2:c.1457T>C
NM_001195800.2:c.1076T>C
NM_001195803.2:c.1199T>C
NP_000518.1:p.Val527Ala
NP_000518.1:p.Val527Ala
NP_001182727.1:p.Val527Ala
NP_001182728.1:p.Val486Ala
NP_001182729.1:p.Val359Ala
NP_001182732.1:p.Val400Ala
LRG_274t1:c.1580T>C
LRG_274:g.29376T>C
LRG_274p1:p.Val527Ala
NC_000019.9:g.11224432T>C
NM_000527.4:c.1580T>C

Protein change:

V359A

Links:

dbSNP: rs730882107

NCBI 1000 Genomes Browser:

rs730882107

Molecular consequence:

NM_000527.5:c.1580T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1580T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1457T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1076T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1199T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002792274	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 16, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004822481	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25647241, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002792274

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 16, 2021)

unknown

clinical testing

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

SCV004822481

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	10	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.

Thormaehlen AS, Schuberth C, Won HH, Blattmann P, Joggerst-Thomalla B, Theiss S, Asselta R, Duga S, Merlini PA, Ardissino D, Lander ES, Gabriel S, Rader DJ, Peloso GM, Pepperkok R, Kathiresan S, Runz H.

PLoS Genet. 2015 Feb;11(2):e1004855. doi: 10.1371/journal.pgen.1004855. Erratum in: PLoS Genet. 2015 Mar 17;11(3):e1005060. doi: 10.1371/journal.pgen.1005060.

PubMed [citation]

PMID:: 25647241
PMCID:: PMC4409815

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 Fulgent Genetics, Fulgent Genetics, SCV002792274.1

#	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, SCV004822481.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant (also known as p.Val506Ala in the mature protein) replaces valine with alanine at codon 527 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR protein function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 19/251244 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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		10	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine