NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 3, 2021
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:: RCV001293737.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)]

NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)

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.1327T>C (p.Trp443Arg)

HGVS:

NC_000019.10:g.11113418T>C
NG_009060.1:g.29038T>C
NM_000527.5:c.1327T>CMANE SELECT
NM_001195798.2:c.1327T>C
NM_001195799.2:c.1204T>C
NM_001195800.2:c.823T>C
NM_001195803.2:c.946T>C
NP_000518.1:p.Trp443Arg
NP_001182727.1:p.Trp443Arg
NP_001182728.1:p.Trp402Arg
NP_001182729.1:p.Trp275Arg
NP_001182732.1:p.Trp316Arg
LRG_274t1:c.1327T>C
LRG_274:g.29038T>C
NC_000019.9:g.11224094T>C
NM_000527.4:c.1327T>C

Protein change:

W275R

Links:

dbSNP: rs773566855

NCBI 1000 Genomes Browser:

rs773566855

Molecular consequence:

NM_000527.5:c.1327T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1327T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1204T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.823T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.946T>C - 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
SCV001482449	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (2) [See all records that cite these PMIDs] 29261184, 25741868
SCV002183751	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 3, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1301956, 9664576, 9727746, 11196104, 22390909, 15477777, 28290784, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001482449

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

research

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

SCV002183751

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 3, 2021)

germline

clinical testing

PubMed (8)
[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	yes	1	not provided	not provided	1	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis.

Chora JR, Medeiros AM, Alves AC, Bourbon M.

Genet Med. 2018 Jun;20(6):591-598. doi: 10.1038/gim.2017.151. Epub 2017 Oct 26.

PubMed [citation]

PMID:: 29261184

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

See all PubMed Citations (10)

Details of each submission

From Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine, SCV001482449.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002183751.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp443 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 9664576, 9727746, 11196104, 22390909). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 998052). This variant is also known as W422R. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 15477777, 28290784). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs773566855, ExAC 0.002%). This sequence change replaces tryptophan with arginine at codon 443 of the LDLR protein (p.Trp443Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine.

#	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: Nov 3, 2024

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