NM_000527.5(LDLR):c.1408A>G (p.Ser470Gly) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 29, 2024
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:: RCV003766118.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1408A>G (p.Ser470Gly)]

NM_000527.5(LDLR):c.1408A>G (p.Ser470Gly)

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.1408A>G (p.Ser470Gly)

HGVS:

NC_000019.10:g.11113584A>G
NG_009060.1:g.29204A>G
NM_000527.5:c.1408A>GMANE SELECT
NM_001195798.2:c.1408A>G
NM_001195799.2:c.1285A>G
NM_001195800.2:c.904A>G
NM_001195803.2:c.1027A>G
NP_000518.1:p.Ser470Gly
NP_000518.1:p.Ser470Gly
NP_001182727.1:p.Ser470Gly
NP_001182728.1:p.Ser429Gly
NP_001182729.1:p.Ser302Gly
NP_001182732.1:p.Ser343Gly
LRG_274t1:c.1408A>G
LRG_274:g.29204A>G
LRG_274p1:p.Ser470Gly
NC_000019.9:g.11224260A>G
NM_000527.4:c.1408A>G

Protein change:

S302G

Links:

dbSNP: rs1057516128

NCBI 1000 Genomes Browser:

rs1057516128

Molecular consequence:

NM_000527.5:c.1408A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1408A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1285A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.904A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1027A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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TNFAIP8L3 AND (alive[prop]) (623)
Gene
PIEZO1-AS1 PIEZO1 antisense RNA 1 [Homo sapiens]
PIEZO1-AS1 PIEZO1 antisense RNA 1 [Homo sapiens]
Gene ID:339059

Gene
LOC339059 AND (alive[prop]) (1)
Gene
C11orf68 AND (alive[prop]) (658)
Gene
NIPAL3 AND (alive[prop]) (643)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004685389	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27765764, 23130880, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004685389

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

PubMed (3)
[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

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27765764

Mutation detection in Croatian patients with familial hypercholesterolemia.

Pećin I, Whittall R, Futema M, Sertić J, Reiner Z, Leigh SE, Humphries SE.

Ann Hum Genet. 2013 Jan;77(1):22-30. doi: 10.1111/j.1469-1809.2012.00735.x. Epub 2012 Nov 6.

PubMed [citation]

PMID:: 23130880

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004685389.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 470 of the LDLR protein (p.Ser470Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familiar hypercholesterolemia (PMID: 27765764; Invitae). ClinVar contains an entry for this variant (Variation ID: 369856). 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 not expected to disrupt LDLR protein function with a negative predictive value of 95%. This variant disrupts the p.Ser470 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23130880; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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