NM_000527.5(LDLR):c.1562C>T (p.Ala521Val) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 30, 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:: RCV000475963.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1562C>T (p.Ala521Val)]

NM_000527.5(LDLR):c.1562C>T (p.Ala521Val)

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.1562C>T (p.Ala521Val)

HGVS:

NC_000019.10:g.11113738C>T
NG_009060.1:g.29358C>T
NM_000527.5:c.1562C>TMANE SELECT
NM_001195798.2:c.1562C>T
NM_001195799.2:c.1439C>T
NM_001195800.2:c.1058C>T
NM_001195803.2:c.1181C>T
NP_000518.1:p.Ala521Val
NP_000518.1:p.Ala521Val
NP_001182727.1:p.Ala521Val
NP_001182728.1:p.Ala480Val
NP_001182729.1:p.Ala353Val
NP_001182732.1:p.Ala394Val
LRG_274t1:c.1562C>T
LRG_274:g.29358C>T
LRG_274p1:p.Ala521Val
NC_000019.9:g.11224414C>T
NM_000527.4:c.1562C>T

Protein change:

A353V

Links:

dbSNP: rs770696696

NCBI 1000 Genomes Browser:

rs770696696

Molecular consequence:

NM_000527.5:c.1562C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1562C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1439C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1058C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1181C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544643	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18718593, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544643

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 30, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population.

Miyake Y, Yamamura T, Sakai N, Miyata T, Kokubo Y, Yamamoto A.

Atherosclerosis. 2009 Mar;203(1):153-60. doi: 10.1016/j.atherosclerosis.2008.07.005. Epub 2008 Jul 15.

PubMed [citation]

PMID:: 18718593

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544643.7

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 521 of the LDLR protein (p.Ala521Val). This variant is present in population databases (rs770696696, gnomAD 0.003%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 18718593; Invitae). This variant is also known as A500V. ClinVar contains an entry for this variant (Variation ID: 406164). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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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