NM_000527.5(LDLR):c.394C>T (p.Arg132Trp) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 31, 2021
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:: RCV001988908.5

Allele description [Variation Report for NM_000527.5(LDLR):c.394C>T (p.Arg132Trp)]

NM_000527.5(LDLR):c.394C>T (p.Arg132Trp)

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.394C>T (p.Arg132Trp)

HGVS:

NC_000019.10:g.11105300C>T
NG_009060.1:g.20920C>T
NM_000527.5:c.394C>TMANE SELECT
NM_001195798.2:c.394C>T
NM_001195799.2:c.271C>T
NM_001195800.2:c.314-2092C>T
NM_001195803.2:c.314-1265C>T
NP_000518.1:p.Arg132Trp
NP_001182727.1:p.Arg132Trp
NP_001182728.1:p.Arg91Trp
LRG_274:g.20920C>T
NC_000019.9:g.11215976C>T

Protein change:

R132W

Links:

dbSNP: rs368978979

NCBI 1000 Genomes Browser:

rs368978979

Molecular consequence:

NM_001195800.2:c.314-2092C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1265C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.394C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.394C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.271C>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
SCV002278672	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 31, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27784735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002278672

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 31, 2021)

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

Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.

Sánchez-Hernández RM, Civeira F, Stef M, Perez-Calahorra S, Almagro F, Plana N, Novoa FJ, Sáenz-Aranzubía P, Mosquera D, Soler C, Fuentes FJ, Brito-Casillas Y, Real JT, Blanco-Vaca F, Ascaso JF, Pocovi M.

Circ Cardiovasc Genet. 2016 Dec;9(6):504-510. doi: 10.1161/CIRCGENETICS.116.001545. Epub 2016 Oct 26.

PubMed [citation]

PMID:: 27784735

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, SCV002278672.2

#	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 arginine with tryptophan at codon 132 of the LDLR protein (p.Arg132Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs368978979, ExAC 0.002%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 27784735). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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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