NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV000791422.12

Allele description [Variation Report for NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys)]

NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys)

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.1329G>C (p.Trp443Cys)

Other names:

FH North Platt

HGVS:

NC_000019.10:g.11113420G>C
NG_009060.1:g.29040G>C
NM_000527.5:c.1329G>CMANE SELECT
NM_001195798.2:c.1329G>C
NM_001195799.2:c.1206G>C
NM_001195800.2:c.825G>C
NM_001195803.2:c.948G>C
NP_000518.1:p.Trp443Cys
NP_000518.1:p.Trp443Cys
NP_001182727.1:p.Trp443Cys
NP_001182728.1:p.Trp402Cys
NP_001182729.1:p.Trp275Cys
NP_001182732.1:p.Trp316Cys
LRG_274t1:c.1329G>C
LRG_274:g.29040G>C
LRG_274p1:p.Trp443Cys
NC_000019.9:g.11224096G>C
NM_000527.4:c.1329G>C
P01130:p.Trp443Cys
c.1329G>C

Protein change:

W275C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001399; UniProtKB: P01130#VAR_005389; dbSNP: rs879254867

NCBI 1000 Genomes Browser:

rs879254867

Molecular consequence:

NM_000527.5:c.1329G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1329G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1206G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.825G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.948G>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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Oenococcus oeni IOEB_S277 contig00059, whole genome shotgun sequence
Oenococcus oeni IOEB_S277 contig00059, whole genome shotgun sequence
gi|696242444|ref|NZ_AZKD01000058.1| WGS:NZ_AZKD01|contig00059

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544664	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301956, 9664576, 9727746, 11196104, 22390909, 28458923, 28492532
SCV001346787	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301956, 9664576, 9727746, 11196104, 22390909, 33740630, 25741868
SCV002511543	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11196104, 23833242, 33740630 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544664

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 1, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001346787

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 29, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002511543

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 5, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia.

Korneva VA, Kuznetsova TY, Bogoslovskaya TY, Polyakov DS, Vasilyev VB, Orlov AV, Mandelshtam MY.

Cholesterol. 2017;2017:9375818. doi: 10.1155/2017/9375818. Epub 2017 Mar 28.

PubMed [citation]

PMID:: 28458923
PMCID:: PMC5387824

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

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544664.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 443 of the LDLR protein (p.Trp443Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 9664576, 9727746, 11196104, 22390909). This variant is also known as p.Trp422Cys. ClinVar contains an entry for this variant (Variation ID: 251792). 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 with a positive predictive value of 95%. This variant disrupts the p.Trp443 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 28458923), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV001346787.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant (also known as p.Trp422Cys in the mature protein) replaces tryptophan with cysteine at codon 443 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that human cells compound heterozygous for this variant and p.Pro685Leu show 5-15% LDLR activity (PMID: 1301956). This variant has been reported in over 90 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11196104, 9664576, 9727746, 22390909, 33740630). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: LDLR c.1329G>C (p.Trp443Cys) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251246 control chromosomes (gnomAD). c.1329G>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Weiss_2000, Kusters_2013, Leren_2021). These data indicate that the variant is very likely to be associated with disease. Twelve ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Oct 20, 2024

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