NM_000527.5(LDLR):c.907C>T (p.Arg303Trp) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Jun 8, 2021
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:: RCV000238462.21

Allele description [Variation Report for NM_000527.5(LDLR):c.907C>T (p.Arg303Trp)]

NM_000527.5(LDLR):c.907C>T (p.Arg303Trp)

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.907C>T (p.Arg303Trp)

Other names:

NM_000527.5(LDLR):c.907C>T

HGVS:

NC_000019.10:g.11107481C>T
NG_009060.1:g.23101C>T
NM_000527.5:c.907C>TMANE SELECT
NM_001195798.2:c.907C>T
NM_001195799.2:c.784C>T
NM_001195800.2:c.403C>T
NM_001195803.2:c.526C>T
NP_000518.1:p.Arg303Trp
NP_000518.1:p.Arg303Trp
NP_001182727.1:p.Arg303Trp
NP_001182728.1:p.Arg262Trp
NP_001182729.1:p.Arg135Trp
NP_001182732.1:p.Arg176Trp
LRG_274t1:c.907C>T
LRG_274:g.23101C>T
LRG_274p1:p.Arg303Trp
NC_000019.9:g.11218157C>T
NM_000527.4:c.907C>T
c.907C>T
p.Arg303Trp

Protein change:

R135W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000512; dbSNP: rs151207122

NCBI 1000 Genomes Browser:

rs151207122

Molecular consequence:

NM_000527.5:c.907C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.907C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.784C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.403C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.526C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295044	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,
SCV000606263	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001432670	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 10, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001960917	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Uncertain significance (Jun 8, 2021)	germline	curation	Citation Link,
SCV002782736	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 17, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820229	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9544746, 28965616, 31345425, 32977124, 34040191, 36507290, 25741868

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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	literature only, research
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Low density lipoprotein receptor mutations in a selected population of individuals with moderate hypercholesterolemia.

Arca M, Jokinen E.

Atherosclerosis. 1998 Jan;136(1):187-94.

PubMed [citation]

PMID:: 9544746

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study.

Pirillo A, Garlaschelli K, Arca M, Averna M, Bertolini S, Calandra S, Tarugi P, Catapano AL; LIPIGEN Group..

Atheroscler Suppl. 2017 Oct;29:17-24. doi: 10.1016/j.atherosclerosissup.2017.07.002.

PubMed [citation]

PMID:: 28965616

See all PubMed Citations (7)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295044.2

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606263.1

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

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432670.1

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960917.1

#	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.907C>T (p.Arg303Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP3 - REVEL = 0.815. It is above 0.75, so PP3 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

From Fulgent Genetics, Fulgent Genetics, SCV002782736.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004820229.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant (also known as p.Arg282Trp in the mature protein) replaces arginine with tryptophan at codon 303 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9544746, 28965616, 31345425, 34040191). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 32977124, 36507290). This variant has been identified in 13/282676 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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