NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 7, 2022
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:: RCV000518174.14

Allele description [Variation Report for NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp)]

NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp)

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.1783C>T (p.Arg595Trp)

Other names:

NM_000527.5(LDLR):c.1783C>T

HGVS:

NC_000019.10:g.11116936C>T
NG_009060.1:g.32556C>T
NM_000527.5:c.1783C>TMANE SELECT
NM_001195798.2:c.1783C>T
NM_001195799.2:c.1660C>T
NM_001195800.2:c.1279C>T
NM_001195803.2:c.1402C>T
NP_000518.1:p.Arg595Trp
NP_000518.1:p.Arg595Trp
NP_001182727.1:p.Arg595Trp
NP_001182728.1:p.Arg554Trp
NP_001182729.1:p.Arg427Trp
NP_001182732.1:p.Arg468Trp
LRG_274t1:c.1783C>T
LRG_274:g.32556C>T
LRG_274p1:p.Arg595Trp
NC_000019.9:g.11227612C>T
NM_000527.3:c.1783C>T
NM_000527.4:c.1783C>T
P01130:p.Arg595Trp
c.1783C>T
p.ARG595TRP

Protein change:

R427W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000239; UniProtKB: P01130#VAR_072856

Molecular consequence:

NM_000527.5:c.1783C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1783C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1660C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1279C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1402C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000614004	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Jun 16, 2017)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 15890894, 25637381, 15241806, 28502510, 27578128, 15823288, 16250003, 20538126, 25461735, 28502495, 12492446, 16627557, 26467025
SCV001433287	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 16, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002526489	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 7, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000614004

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Jun 16, 2017)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV001433287

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 16, 2020)

germline

clinical testing

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

SCV002526489

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 7, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Reliable low-density DNA array based on allele-specific probes for detection of 118 mutations causing familial hypercholesterolemia.

Tejedor D, Castillo S, Mozas P, Jiménez E, López M, Tejedor MT, Artieda M, Alonso R, Mata P, Simón L, Martínez A, Pocoví M; Spanish FH Group..

Clin Chem. 2005 Jul;51(7):1137-44. Epub 2005 May 12.

PubMed [citation]

PMID:: 15890894

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

See all PubMed Citations (14)

Details of each submission

From Athena Diagnostics, SCV000614004.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

#	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 Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV001433287.1

#	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 GeneDx, SCV002526489.3

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a pathogenic variant by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar Variant ID#171218; SCV001960931.1); Also known as p.(R574W); This variant is associated with the following publications: (PMID: 25637381, 28502510, 29172679, 28965616, 15823288, 16250003, 28502495, 30586733, 31491741, 31447099, 33740630, 34037665, 29353225, 32331935, 11737238, 15241806, 27578128, 30583242, 34906454, 34526433, 33994402, 34176852, 20538126, 25461735, 27784735)

#	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

Last Updated: Aug 25, 2024

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