NM_000527.5(LDLR):c.2039T>C (p.Leu680Pro) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 26, 2022
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:: RCV001036739.8

Allele description [Variation Report for NM_000527.5(LDLR):c.2039T>C (p.Leu680Pro)]

NM_000527.5(LDLR):c.2039T>C (p.Leu680Pro)

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.2039T>C (p.Leu680Pro)

HGVS:

NC_000019.10:g.11120421T>C
NG_009060.1:g.36041T>C
NM_000527.5:c.2039T>CMANE SELECT
NM_001195798.2:c.2039T>C
NM_001195799.2:c.1916T>C
NM_001195800.2:c.1535T>C
NM_001195803.2:c.1606+188T>C
NP_000518.1:p.Leu680Pro
NP_000518.1:p.Leu680Pro
NP_001182727.1:p.Leu680Pro
NP_001182728.1:p.Leu639Pro
NP_001182729.1:p.Leu512Pro
LRG_274t1:c.2039T>C
LRG_274:g.36041T>C
LRG_274p1:p.Leu680Pro
NC_000019.9:g.11231097T>C
NM_000527.4:c.2039T>C

Protein change:

L512P

Links:

dbSNP: rs1555807379

NCBI 1000 Genomes Browser:

rs1555807379

Molecular consequence:

NM_001195803.2:c.1606+188T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2039T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2039T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1916T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1535T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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apolipoprotein E isoform b precursor [Homo sapiens]
apolipoprotein E isoform b precursor [Homo sapiens]
gi|705044063|ref|NP_001289618.1|

Protein
PREDICTED: Homo sapiens ryanodine receptor 2 (RYR2), transcript variant X13, mRN...
PREDICTED: Homo sapiens ryanodine receptor 2 (RYR2), transcript variant X13, mRNA
gi|2462512299|ref|XM_054338104.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001200117	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 26, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27824480, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001200117

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 26, 2022)

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

The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.

Gabčová D, Vohnout B, Staníková D, Hučková M, Kadurová M, Debreová M, Kozárová M, Fábryová Ľ, Staník J, Klimeš I, Rašlová K, Gašperiková D.

Physiol Res. 2017 Mar 31;66(1):75-84. Epub 2016 Nov 8.

PubMed [citation]

PMID:: 27824480

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, SCV001200117.5

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

Description

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: 440674). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 27824480). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 680 of the LDLR protein (p.Leu680Pro). 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.

#	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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