NM_000527.5(LDLR):c.1210A>C (p.Thr404Pro) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 28, 2023
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:: RCV000238140.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1210A>C (p.Thr404Pro)]

NM_000527.5(LDLR):c.1210A>C (p.Thr404Pro)

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.1210A>C (p.Thr404Pro)

Other names:

NM_000527.5(LDLR):c.1210A>C

HGVS:

NC_000019.10:g.11113301A>C
NG_009060.1:g.28921A>C
NM_000527.5:c.1210A>CMANE SELECT
NM_001195798.2:c.1210A>C
NM_001195799.2:c.1087A>C
NM_001195800.2:c.706A>C
NM_001195803.2:c.829A>C
NP_000518.1:p.Thr404Pro
NP_000518.1:p.Thr404Pro
NP_001182727.1:p.Thr404Pro
NP_001182728.1:p.Thr363Pro
NP_001182729.1:p.Thr236Pro
NP_001182732.1:p.Thr277Pro
LRG_274t1:c.1210A>C
LRG_274:g.28921A>C
LRG_274p1:p.Thr404Pro
NC_000019.9:g.11223977A>C
NM_000527.4:c.1210A>C
P01130:p.Thr404Pro
c.1210A>C

Protein change:

T236P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001377; UniProtKB: P01130#VAR_072846; dbSNP: rs879254834

NCBI 1000 Genomes Browser:

rs879254834

Molecular consequence:

NM_000527.5:c.1210A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1210A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1087A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.706A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.829A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

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F-box family protein [Arabidopsis thaliana]
F-box family protein [Arabidopsis thaliana]
gi|30679626|ref|NP_179225.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295301	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8697568, 15199436 Citation Link,
SCV000782909	Robarts Research Institute, Western University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004022458	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Apr 28, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295301

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV000782909

Robarts Research Institute, Western University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 2, 2018)

germline

clinical testing

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

SCV004022458

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Apr 28, 2023)

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	2	not provided	not provided	2	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

High sensitivity of the single-strand conformation polymorphism method for detecting sequence variations in the low-density lipoprotein receptor gene validated by DNA sequencing.

Jensen HK, Jensen LG, Hansen PS, Faergeman O, Gregersen N.

Clin Chem. 1996 Aug;42(8 Pt 1):1140-6.

PubMed [citation]

PMID:: 8697568

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

See all PubMed Citations (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295301.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	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
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Robarts Research Institute, Western University, SCV000782909.1

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

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022458.1

#	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.1210A>C (p.Thr404Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, 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: PM2: This variant is absent from gnomAD v2.1.1 PP3: REVEL= 0.93 PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite criteria for FH from PMID 8697568, after alternative causes of high cholesterol were excluded.

#	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 13, 2023

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