NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: May 30, 2022
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:: RCV000210245.18

Allele description [Variation Report for NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln)]

NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln)

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.2252G>A (p.Arg751Gln)

Other names:

NM_000527.5(LDLR):c.2252G>A

HGVS:

NC_000019.10:g.11123285G>A
NG_009060.1:g.38905G>A
NM_000527.5:c.2252G>AMANE SELECT
NM_001195798.2:c.2252G>A
NM_001195799.2:c.2129G>A
NM_001195800.2:c.1748G>A
NM_001195803.2:c.1718G>A
NP_000518.1:p.Arg751Gln
NP_000518.1:p.Arg751Gln
NP_001182727.1:p.Arg751Gln
NP_001182728.1:p.Arg710Gln
NP_001182729.1:p.Arg583Gln
NP_001182732.1:p.Arg573Gln
LRG_274t1:c.2252G>A
LRG_274:g.38905G>A
LRG_274p1:p.Arg751Gln
NC_000019.9:g.11233961G>A
NM_000527.4:c.2252G>A
c.2252G>A

Protein change:

R573Q

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001084; dbSNP: rs200142970

NCBI 1000 Genomes Browser:

rs200142970

Molecular consequence:

NM_000527.5:c.2252G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2252G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1718G>A - 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
SCV000266313	Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT	criteria provided, single submitter (Mayo Cardiovascular Biomarkers Research Laboratory LDLR variant interpretation criteria, 2015)	Uncertain significance (Aug 31, 2015)	germline	research	PubMed (1) [See all records that cite this PMID] Kullo Lab Assertion Criteria_01072016.pdf, Citation Link,
SCV000295926	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16159606, 16250003 Citation Link,
SCV000606620	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV002568110	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (May 30, 2022)	germline	curation	Citation Link,
SCV004818517	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16159606, 16250003, 28145427, 33955087, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	34	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	germline	yes	2	not provided	not provided	2	not provided	literature only
White	germline	no	not provided	not provided	not provided	1013	not provided	research

Citations

PubMed

Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate.

Graham CA, McIlhatton BP, Kirk CW, Beattie ED, Lyttle K, Hart P, Neely RD, Young IS, Nicholls DP.

Atherosclerosis. 2005 Oct;182(2):331-40.

PubMed [citation]

PMID:: 16159606

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (5)

Details of each submission

From Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT, SCV000266313.2

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

Description

MAF =<0.3%, LDL-C >=160 mg/dL

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	1013	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000295926.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	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
2	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, SCV000606620.1

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002568110.1

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

Description

NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1). PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases (1 case published in PMID: 16250003 (Fouchier et al., 2005), Netherlands; 1 case published in PMID: 16159606 (Graham et al., 2005), United Kingdom). PP4 - Variant meets PM2. PMID: 16159606 - 1 case who fulfills Simon-Broome criteria for FH.

#	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 All of Us Research Program, National Institutes of Health, SCV004818517.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	34	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with glutamine at codon 751 of the LDLR protein. This variant is also known as p.Arg730Gln in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with familial hypercholesterolemia (PMID: 16159606, 16250003, 28145427, 33955087). This variant has also been identified in 22/282676 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		34	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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