NM_000527.5(LDLR):c.1361C>A (p.Thr454Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Jan 31, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000237982.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1361C>A (p.Thr454Asn)]

NM_000527.5(LDLR):c.1361C>A (p.Thr454Asn)

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.1361C>A (p.Thr454Asn)

Other names:

NM_000527.5(LDLR):c.1361C>A

HGVS:

NC_000019.10:g.11113537C>A
NG_009060.1:g.29157C>A
NM_000527.5:c.1361C>AMANE SELECT
NM_001195798.2:c.1361C>A
NM_001195799.2:c.1238C>A
NM_001195800.2:c.857C>A
NM_001195803.2:c.980C>A
NP_000518.1:p.Thr454Asn
NP_000518.1:p.Thr454Asn
NP_001182727.1:p.Thr454Asn
NP_001182728.1:p.Thr413Asn
NP_001182729.1:p.Thr286Asn
NP_001182732.1:p.Thr327Asn
LRG_274t1:c.1361C>A
LRG_274:g.29157C>A
LRG_274p1:p.Thr454Asn
NC_000019.9:g.11224213C>A
NM_000527.4:c.1361C>A
P01130:p.Thr454Asn
c.1361C>A

Protein change:

T286N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000844; UniProtKB: P01130#VAR_072849; dbSNP: rs879254879

NCBI 1000 Genomes Browser:

rs879254879

Molecular consequence:

NM_000527.5:c.1361C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1361C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1238C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.857C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.980C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295394	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000607595	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 25378237
SCV002506342	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Jan 31, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295394

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV000607595

Fundacion Hipercolesterolemia Familiar - SAFEHEART

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 1, 2016)

germline

research

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

SCV002506342

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Likely pathogenic
(Jan 31, 2022)

germline

curation

Citation Link

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	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation

Citations

PubMed

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, Pocoví M.

Hum Mutat. 2004 Aug;24(2):187.

PubMed [citation]

PMID:: 15241806

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 (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295394.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607595.1

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

Description

"Heterologous cells (CHO), FACS assays"

PubMed [ID: 25378237]

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506342.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000527.5(LDLR):c.1361C>A (p.Thr454Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - Level 1 FS: Etxebarria et al. 2015 (PMID 25378237): Heterologous cells (CHO) with FACS - results: 65% LDL-LDLR binding, uptake and cell surface LDLR --- activity is below 70% of wild-type, so PS3 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in 1 index case with MEDPED clinical criteria of FH (45 year old female with TC 398mg/dl) from PMID: 19007590 (Civeira et al. 2008), Spain; so PP4 is met.

#	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: Aug 5, 2023

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