NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 15, 2023
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:: RCV003581635.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser)]

NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser)

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.1906G>A (p.Gly636Ser)

Other names:

NM_000527.5(LDLR):c.1906G>A; p.Gly636Ser

HGVS:

NC_000019.10:g.11120152G>A
NG_009060.1:g.35772G>A
NM_000527.5:c.1906G>AMANE SELECT
NM_001195798.2:c.1906G>A
NM_001195799.2:c.1783G>A
NM_001195800.2:c.1402G>A
NM_001195803.2:c.1525G>A
NP_000518.1:p.Gly636Ser
NP_001182727.1:p.Gly636Ser
NP_001182728.1:p.Gly595Ser
NP_001182729.1:p.Gly468Ser
NP_001182732.1:p.Gly509Ser
LRG_274t1:c.1906G>A
LRG_274:g.35772G>A
NC_000019.9:g.11230828G>A
NM_000527.4:c.1906G>A
c.1906G>A

Protein change:

G468S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000905; dbSNP: rs764550980

NCBI 1000 Genomes Browser:

rs764550980

Molecular consequence:

NM_000527.5:c.1906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1783G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1402G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1525G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Transcriptional factor B3 family protein [Arabidopsis thaliana]
Transcriptional factor B3 family protein [Arabidopsis thaliana]
gi|18417840|ref|NP_567880.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004265556	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16542394, 24671153, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004265556

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 15, 2023)

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

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]

PMID:: 16542394

Functional characterization of two low-density lipoprotein receptor gene mutations in two Chinese patients with familial hypercholesterolemia.

Wang H, Xu S, Sun L, Pan X, Yang S, Wang L.

PLoS One. 2014;9(3):e92703. doi: 10.1371/journal.pone.0092703.

PubMed [citation]

PMID:: 24671153
PMCID:: PMC3966815

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004265556.1

#	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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 636 of the LDLR protein (p.Gly636Ser). This variant is present in population databases (rs764550980, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 16542394). This variant is also known as G615S. ClinVar contains an entry for this variant (Variation ID: 252109). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly615 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24671153). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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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