NM_000527.5(LDLR):c.2231G>A (p.Arg744Gln) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Benign/Likely benign (8 submissions)
Last evaluated:: Oct 1, 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:: RCV000058922.22

Allele description

NM_000527.5(LDLR):c.2231G>A (p.Arg744Gln)

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.2231G>A (p.Arg744Gln)

Other names:

R744R; NM_000527.5(LDLR):c.2231G>A

HGVS:

NC_000019.10:g.11123264G>A
NG_009060.1:g.38884G>A
NM_000527.5:c.2231G>AMANE SELECT
NM_001195798.2:c.2231G>A
NM_001195799.2:c.2108G>A
NM_001195800.2:c.1727G>A
NM_001195803.2:c.1697G>A
NP_000518.1:p.Arg744Gln
NP_000518.1:p.Arg744Gln
NP_001182727.1:p.Arg744Gln
NP_001182728.1:p.Arg703Gln
NP_001182729.1:p.Arg576Gln
NP_001182732.1:p.Arg566Gln
LRG_274t1:c.2231G>A
LRG_274:g.38884G>A
LRG_274p1:p.Arg744Gln
NC_000019.9:g.11233940G>A
NM_000527.4:c.2231G>A
c.2231G>A

Protein change:

R566Q

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000588;

Molecular consequence:

NM_000527.5:c.2231G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2231G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2108G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1727G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1697G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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ln7
ln7

biosample
TetR/AcrR family transcriptional regulator [Bacillus subtilis subsp. subtilis]
TetR/AcrR family transcriptional regulator [Bacillus subtilis subsp. subtilis]
gi|1491879719|gnl|PRJNA495409|D9C08 5|gb|AYL03121.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000090443	SNPedia	no classification provided	not provided	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV000189587	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]
SCV000697223	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jun 1, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 27153395, 20506408, 24956927, 16542394, 17539906, 27578104, 15523646, 18325082, 16250003 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000888165	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (Dec 23, 2022)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 25487149, 20506408, 27153395, 26892515, 25647241, 9409298, 12436241, 16250003, 15823288, 35047021, 26036859, 26467025
SCV000977871	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jun 18, 2018)	germline	clinical testing	Citation Link,
SCV000987540	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001151673	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Oct 1, 2023)	germline	clinical testing	Citation Link,
SCV001963279	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Likely benign	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	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

The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine.

Biesecker LG, Mullikin JC, Facio FM, Turner C, Cherukuri PF, Blakesley RW, Bouffard GG, Chines PS, Cruz P, Hansen NF, Teer JK, Maskeri B, Young AC; NISC Comparative Sequencing Program., Manolio TA, Wilson AF, Finkel T, Hwang P, Arai A, Remaley AT, Sachdev V, Shamburek R, et al.

Genome Res. 2009 Sep;19(9):1665-74. doi: 10.1101/gr.092841.109. Epub 2009 Jul 14.

PubMed [citation]

PMID:: 19602640
PMCID:: PMC2752125

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study.

Norsworthy PJ, Vandrovcova J, Thomas ER, Campbell A, Kerr SM, Biggs J, Game L, Soutar AK, Smith BH, Dominiczak AF, Porteous DJ, Morris AD, Scotland G, Aitman TJ.

BMC Med Genet. 2014 Jun 23;15:70. doi: 10.1186/1471-2350-15-70.

PubMed [citation]

PMID:: 24956927
PMCID:: PMC4083361

See all PubMed Citations (20)

Details of each submission

From SNPedia, SCV000090443.1

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

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

From Dept. of Genetics and Pharmacogenomics, Merck Research Labs, SCV000189587.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697223.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: The LDLR c.2231G>A (p.Arg744Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is located outside of any known functional domain or repeat. 4/4 in silico tools predict benign outcome for this variant (SNP&GO was not used due to a low reliability index), however no experimental studies were published at the time of evaluation (ACMG BP4). The variant of interest has been identified in a large, broad control datasets of ExAC at a frequency of 0.0008 (99/121250 chrs tested), reaching the 0.0011 in several sub-populations (South Asians and European NF) including 1 homozygote. Although the observed frequency is similar to the estimated maximal expected allele frequency of a pathogenic LDLR variant (~0.001), thus supporting benign interpretation, the information on lipid profiling in these individuals is not available for individual review. The variant of interest was reported in multiple patients with elevated cholesterol level, including patient(s) carrying a known pathogenic variant APOB p.R3500Q (ACMG BP5), in whom lipid profiling results were not significantly different from data observed in patients carrying APOB R3500Q alone (Brusgaard, 2006) (ACMG BP5). In addition, per Dutch FH-database, cholesterol levels of R723Q positive and R723Q negative relatives are virtually similar (ACMG BS4), again favoring benign classification. The c.2231G>A was identified heterozygously in a healthy Caucasian adult undergoing carrier screening (ACMG BS2). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign (ACMG BP6). Considering all evidence the variant was conservatively classified as Likely Benign until additional evidence supporting its presence in normolipedimic control subjects is obtained.ACMG Classification: BRationale for Pathogenicity: none. Rationale for being Benign: BS2, BS4, BP4, BP5; BP6 was not engaged due to discordant classifications.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000888165.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

#	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 GeneDx, SCV000977871.1

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987540.1

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001151673.15

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

Description

LDLR: BP4, BS1

#	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		1	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001963279.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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