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

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 26, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000791388.19

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]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000825564	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9544746, 24507775, 28965616, 34040191, 28492532
SCV001346462	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 7, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9544746, 28965616, 31345425, 32977124, 34040191, 36507290, 25741868
SCV002086393	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 24, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000825564

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 26, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001346462

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 7, 2023)

germline

clinical testing

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

SCV002086393

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 24, 2020)

germline

clinical testing

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

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

Lange LA, Hu Y, Zhang H, Xue C, Schmidt EM, Tang ZZ, Bizon C, Lange EM, Smith JD, Turner EH, Jun G, Kang HM, Peloso G, Auer P, Li KP, Flannick J, Zhang J, Fuchsberger C, Gaulton K, Lindgren C, Locke A, Manning A, et al.

Am J Hum Genet. 2014 Feb 6;94(2):233-45. doi: 10.1016/j.ajhg.2014.01.010.

PubMed [citation]

PMID:: 24507775
PMCID:: PMC3928660

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 (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000825564.5

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 303 of the LDLR protein (p.Arg303Trp). This variant is present in population databases (rs151207122, gnomAD 0.04%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9544746, 24507775, 28965616, 34040191; Invitae). This variant is also known as p.Arg282Trp and R282W. ClinVar contains an entry for this variant (Variation ID: 161281). 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%. 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, SCV001346462.3

#	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.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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002086393.1

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

Last Updated: Oct 26, 2024

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