NM_000527.5(LDLR):c.1228A>G (p.Arg410Gly) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 28, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001043440.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1228A>G (p.Arg410Gly)]

NM_000527.5(LDLR):c.1228A>G (p.Arg410Gly)

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.1228A>G (p.Arg410Gly)

HGVS:

NC_000019.10:g.11113319A>G
NG_009060.1:g.28939A>G
NM_000527.5:c.1228A>GMANE SELECT
NM_001195798.2:c.1228A>G
NM_001195799.2:c.1105A>G
NM_001195800.2:c.724A>G
NM_001195803.2:c.847A>G
NP_000518.1:p.Arg410Gly
NP_001182727.1:p.Arg410Gly
NP_001182728.1:p.Arg369Gly
NP_001182729.1:p.Arg242Gly
NP_001182732.1:p.Arg283Gly
LRG_274t1:c.1228A>G
LRG_274:g.28939A>G
NC_000019.9:g.11223995A>G
NM_000527.4:c.1228A>G

Protein change:

R242G

Links:

dbSNP: rs2077408020

NCBI 1000 Genomes Browser:

rs2077408020

Molecular consequence:

NM_000527.5:c.1228A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1228A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1105A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.724A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.847A>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
SCV001207187	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 28, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27998977, 23375686, 19062533, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001207187

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 28, 2019)

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

The Proprotein Convertase Subtilisin/Kexin Type 9-resistant R410S Low Density Lipoprotein Receptor Mutation: A NOVEL MECHANISM CAUSING FAMILIAL HYPERCHOLESTEROLEMIA.

Susan-Resiga D, Girard E, Kiss RS, Essalmani R, Hamelin J, Asselin MC, Awan Z, Butkinaree C, Fleury A, Soldera A, Dory YL, Baass A, Seidah NG.

J Biol Chem. 2017 Feb 3;292(5):1573-1590. doi: 10.1074/jbc.M116.769430. Epub 2016 Dec 20.

PubMed [citation]

PMID:: 27998977
PMCID:: PMC5290936

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207187.5

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg410 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27998977, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in an individual affected with clinical features of familial hypercholesterolemia (PMID: 19062533). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 410 of the LDLR protein (p.Arg410Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.

#	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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