NM_000527.5(LDLR):c.1686G>T (p.Trp562Cys) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 11, 2023
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:: RCV003741257.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1686G>T (p.Trp562Cys)]

NM_000527.5(LDLR):c.1686G>T (p.Trp562Cys)

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.1686G>T (p.Trp562Cys)

HGVS:

NC_000019.10:g.11116193G>T
NG_009060.1:g.31813G>T
NM_000527.5:c.1686G>TMANE SELECT
NM_001195798.2:c.1686G>T
NM_001195799.2:c.1563G>T
NM_001195800.2:c.1182G>T
NM_001195803.2:c.1305G>T
NP_000518.1:p.Trp562Cys
NP_001182727.1:p.Trp562Cys
NP_001182728.1:p.Trp521Cys
NP_001182729.1:p.Trp394Cys
NP_001182732.1:p.Trp435Cys
LRG_274t1:c.1686G>T
LRG_274:g.31813G>T
NC_000019.9:g.11226869G>T
NM_000527.4:c.1686G>T
p.(Trp562Cys)

Protein change:

W394C

Links:

dbSNP: rs879254985

NCBI 1000 Genomes Browser:

rs879254985

Molecular consequence:

NM_000527.5:c.1686G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1686G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1563G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1182G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1305G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV004539065	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28965616, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004539065

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 11, 2023)

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

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study.

Pirillo A, Garlaschelli K, Arca M, Averna M, Bertolini S, Calandra S, Tarugi P, Catapano AL; LIPIGEN Group..

Atheroscler Suppl. 2017 Oct;29:17-24. doi: 10.1016/j.atherosclerosissup.2017.07.002.

PubMed [citation]

PMID:: 28965616

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV004539065.1

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 1120247). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 28965616; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 562 of the LDLR protein (p.Trp562Cys).

#	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: Feb 28, 2024

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