NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 18, 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:: RCV000775063.10

Allele description [Variation Report for NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr)]

NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr)

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.1322T>C (p.Ile441Thr)

Other names:

NM_000527.5(LDLR):c.1322T>C; p.Ile441Thr

HGVS:

NC_000019.10:g.11113413T>C
NG_009060.1:g.29033T>C
NM_000527.5:c.1322T>CMANE SELECT
NM_001195798.2:c.1322T>C
NM_001195799.2:c.1199T>C
NM_001195800.2:c.818T>C
NM_001195803.2:c.941T>C
NP_000518.1:p.Ile441Thr
NP_000518.1:p.Ile441Thr
NP_001182727.1:p.Ile441Thr
NP_001182728.1:p.Ile400Thr
NP_001182729.1:p.Ile273Thr
NP_001182732.1:p.Ile314Thr
LRG_274t1:c.1322T>C
LRG_274:g.29033T>C
LRG_274p1:p.Ile441Thr
NC_000019.9:g.11224089T>C
NM_000527.4:c.1322T>C
c.1322T>C

Protein change:

I273T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000186; dbSNP: rs879254862

NCBI 1000 Genomes Browser:

rs879254862

Molecular consequence:

NM_000527.5:c.1322T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1322T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1199T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.818T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.941T>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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Cactus townsendii (31)
Taxonomy
CYBB cytochrome b-245 beta chain [Homo sapiens]
CYBB cytochrome b-245 beta chain [Homo sapiens]
Gene ID:1536

Gene
Gene Links for GEO Profiles (Select 63261462) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000909164	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 9, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001584660	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 18, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11810272, 17087781, 20538126, 25741862, 27206935, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909164

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 9, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001584660

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 18, 2023)

germline

clinical testing

PubMed (6)
[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

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

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

See all PubMed Citations (7)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909164.1

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

Description

Pathogenic variant based on current evidence: This missense variant (also known as p.Ile420Thr in the mature protein) is located in the LDLR type B repeat 2 of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies in CHO cells have shown that this variant causes a near complete loss of LDLR activity (~10% of normal) with retention in the endoplasmic reticulum as the precursor form (PMID: 25741862). This variant has been shown to segregate with hypercholesterolemia in 9 of 10 affected individuals from four different Portuguese families (PMID: 25741862). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Different missense variants at the same codon (p.Ile441Asn and p.Ile 441Met) are considered to be disease-causing. Based on 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001584660.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 441 of the LDLR protein (p.Ile441Thr). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25741862). 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: 251783). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 11810272, 17087781, 20538126, 25741862, 27206935; Invitae). This variant is not present in population databases (gnomAD no frequency).

#	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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