NM_000527.5(LDLR):c.1097A>G (p.Gln366Arg) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 13, 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:: RCV001192511.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1097A>G (p.Gln366Arg)]

NM_000527.5(LDLR):c.1097A>G (p.Gln366Arg)

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.1097A>G (p.Gln366Arg)

HGVS:

NC_000019.10:g.11111550A>G
NG_009060.1:g.27170A>G
NM_000527.5:c.1097A>GMANE SELECT
NM_001195798.2:c.1097A>G
NM_001195799.2:c.974A>G
NM_001195800.2:c.593A>G
NM_001195803.2:c.716A>G
NP_000518.1:p.Gln366Arg
NP_001182727.1:p.Gln366Arg
NP_001182728.1:p.Gln325Arg
NP_001182729.1:p.Gln198Arg
NP_001182732.1:p.Gln239Arg
LRG_274t1:c.1097A>G
LRG_274:g.27170A>G
NC_000019.9:g.11222226A>G
NM_000527.4:c.1097A>G
P01130:p.Gln366Arg
c.1097A>G

Protein change:

Q198R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000411; UniProtKB: P01130#VAR_007985; dbSNP: rs746982741

NCBI 1000 Genomes Browser:

rs746982741

Molecular consequence:

NM_000527.5:c.1097A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1097A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.974A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.593A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.716A>G - 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
SCV001360703	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 29, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8740918, 9016531, 9104431, 12052488, 15199436, 10090473, 8931648 Citation Link,
SCV001575332	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8931648, 9104431, 12052488, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001360703

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 29, 2019)

germline

clinical testing

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

Citation Link,

SCV001575332

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2023)

germline

clinical testing

PubMed (4)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two novel missense mutations in the LDL receptor gene causing familial hypercholesterolemia.

Gundersen KE, Solberg K, Rødningen OK, Tonstad S, Ose L, Berg K, Leren TP.

Clin Genet. 1996 Feb;49(2):85-7.

PubMed [citation]

PMID:: 8740918

Software and database for the analysis of mutations in the human LDL receptor gene.

Varret M, Rabès JP, Collod-Béroud G, Junien C, Boileau C, Béroud C.

Nucleic Acids Res. 1997 Jan 1;25(1):172-80.

PubMed [citation]

PMID:: 9016531
PMCID:: PMC146377

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360703.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: LDLR c.1097A>G (p.Gln366Arg) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251762 control chromosomes, predominantly at a frequency of 4.4e-05 within the Non-Finnish European subpopulation in the gnomAD database. c.1097A>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Gunderson_1996, Lind_2002, Leren_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001575332.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 366 of the LDLR protein (p.Gln366Arg). This variant is present in population databases (rs746982741, gnomAD 0.004%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 8931648, 9104431, 12052488). This variant is also known as Q345R. ClinVar contains an entry for this variant (Variation ID: 251662). 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. 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

Last Updated: Sep 29, 2024

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