NM_000527.5(LDLR):c.1808A>G (p.Lys603Arg) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 2, 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:: RCV003581677.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1808A>G (p.Lys603Arg)]

NM_000527.5(LDLR):c.1808A>G (p.Lys603Arg)

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.1808A>G (p.Lys603Arg)

HGVS:

NC_000019.10:g.11116961A>G
NG_009060.1:g.32581A>G
NM_000527.5:c.1808A>GMANE SELECT
NM_001195798.2:c.1808A>G
NM_001195799.2:c.1685A>G
NM_001195800.2:c.1304A>G
NM_001195803.2:c.1427A>G
NP_000518.1:p.Lys603Arg
NP_000518.1:p.Lys603Arg
NP_001182727.1:p.Lys603Arg
NP_001182728.1:p.Lys562Arg
NP_001182729.1:p.Lys435Arg
NP_001182732.1:p.Lys476Arg
LRG_274t1:c.1808A>G
LRG_274:g.32581A>G
LRG_274p1:p.Lys603Arg
NC_000019.9:g.11227637A>G
NM_000527.4:c.1808A>G

Protein change:

K435R

Links:

dbSNP: rs1302327551

NCBI 1000 Genomes Browser:

rs1302327551

Molecular consequence:

NM_000527.5:c.1808A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1808A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1685A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1304A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1427A>G - 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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transmembrane protein 80 isoform 2 [Homo sapiens]
transmembrane protein 80 isoform 2 [Homo sapiens]
gi|1859470316|ref|NP_001035928.3|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004305574	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 2, 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

SCV004305574

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 2, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, SCV004305574.1

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

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 not expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 440662). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 603 of the LDLR protein (p.Lys603Arg).

#	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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