NM_000527.5(LDLR):c.757C>T (p.Arg253Trp) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jun 27, 2023
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:: RCV000162019.24

Allele description [Variation Report for NM_000527.5(LDLR):c.757C>T (p.Arg253Trp)]

NM_000527.5(LDLR):c.757C>T (p.Arg253Trp)

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.757C>T (p.Arg253Trp)

Other names:

NM_000527.5(LDLR):c.757C>T

HGVS:

NC_000019.10:g.11106627C>T
NG_009060.1:g.22247C>T
NM_000527.5:c.757C>TMANE SELECT
NM_001195798.2:c.757C>T
NM_001195799.2:c.634C>T
NM_001195800.2:c.314-765C>T
NM_001195803.2:c.376C>T
NP_000518.1:p.Arg253Trp
NP_000518.1:p.Arg253Trp
NP_001182727.1:p.Arg253Trp
NP_001182728.1:p.Arg212Trp
NP_001182732.1:p.Arg126Trp
LRG_274t1:c.757C>T
LRG_274:g.22247C>T
LRG_274p1:p.Arg253Trp
NC_000019.9:g.11217303C>T
NM_000527.4:c.757C>T
P01130:p.Arg253Trp
c.757C>T

Protein change:

R126W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000111; UniProtKB: P01130#VAR_013952

Molecular consequence:

NM_001195800.2:c.314-765C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.757C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.757C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.634C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.376C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Endopterygota sp. NZAC 03009281 voucher NZAC:03009281 28S ribosomal RNA gene, pa...
Endopterygota sp. NZAC 03009281 voucher NZAC:03009281 28S ribosomal RNA gene, partial sequence
gi|983652884|gb|KT439693.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000189622	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	no classification provided (in vitro)	not provided	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]
SCV002512868	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 29, 2022)	germline	clinical testing	Citation Link,
SCV004219997	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 27, 2023)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 28220743, 28145427, 27153395, 26036859, 25647241, 25487149, 24507775, 22390909, 20506408, 11810272, 11462246, 11005141, 10882754, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000189622

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

no classification provided

(in vitro)

not provided

not applicable

in vitro

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

SCV002512868

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 29, 2022)

germline

clinical testing

Citation Link,

SCV004219997

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jun 27, 2023)

unknown

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

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	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of mutations causing familial hypercholesterolaemia in black South African patients of different ancestr.

Ibe UK, Whittall R, Humphries SE, Pilcher G, Raal F.

S Afr Med J. 2017 Jan 30;107(2):145-148. doi: 10.7196/SAMJ.2017.v107i2.12022.

PubMed [citation]

PMID:: 28220743

Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals.

Safarova MS, Klee EW, Baudhuin LM, Winkler EM, Kluge ML, Bielinski SJ, Olson JE, Kullo IJ.

Eur J Hum Genet. 2017 Apr;25(4):410-415. doi: 10.1038/ejhg.2016.193. Epub 2017 Feb 1.

PubMed [citation]

PMID:: 28145427
PMCID:: PMC5386413

See all PubMed Citations (14)

Details of each submission

From Dept. of Genetics and Pharmacogenomics, Merck Research Labs, SCV000189622.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (1)

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

From GeneDx, SCV002512868.2

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R232W); This variant is associated with the following publications: (PMID: 25637381, 26036859, 11462246, 11810272, 22390909, 24507775, 25487149, 27044878, 27153395, 32044282, 20506408, 11005141)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219997.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

In the published literature, this variant has been reported in individuals with FH with high or elevated levels of LDL-C (PMIDs: 28220743 (2017), 28145427 (2017), 24507775 (2014), 22390909 (2012), 20506408 (2010), 20506408 (2010)), and in individuals with premature myocardial infarction (PMIDs: 26036859 (2016), 25487149 (2015)). This variant was reported to have no effect on LDL uptake, however further studies are required to determine the global effect of this variant LDLR protein function (PMID: 10882754 (2000)). The frequency of this variant in the general population, 0.001 (26/24970 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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

Last Updated: Oct 13, 2024

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