NM_000527.5(LDLR):c.2026G>C (p.Gly676Arg) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 21, 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:: RCV002518493.3

Allele description [Variation Report for NM_000527.5(LDLR):c.2026G>C (p.Gly676Arg)]

NM_000527.5(LDLR):c.2026G>C (p.Gly676Arg)

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.2026G>C (p.Gly676Arg)

HGVS:

NC_000019.10:g.11120408G>C
NG_009060.1:g.36028G>C
NM_000527.5:c.2026G>CMANE SELECT
NM_001195798.2:c.2026G>C
NM_001195799.2:c.1903G>C
NM_001195800.2:c.1522G>C
NM_001195803.2:c.1606+175G>C
NP_000518.1:p.Gly676Arg
NP_000518.1:p.Gly676Arg
NP_001182727.1:p.Gly676Arg
NP_001182728.1:p.Gly635Arg
NP_001182729.1:p.Gly508Arg
LRG_274t1:c.2026G>C
LRG_274:g.36028G>C
LRG_274p1:p.Gly676Arg
NC_000019.9:g.11231084G>C
NM_000527.4:c.2026G>C
c.2026G>C

Protein change:

G508R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001586; dbSNP: rs745753810

NCBI 1000 Genomes Browser:

rs745753810

Molecular consequence:

NM_001195803.2:c.1606+175G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2026G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2026G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1903G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1522G>C - 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
SCV003443108	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26892515, 27932355, 30526649, 12417285, 31491741, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443108

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 21, 2023)

germline

clinical testing

PubMed (6)
[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 genetic spectrum of familial hypercholesterolemia in south-eastern Poland.

Sharifi M, Walus-Miarka M, Idzior-Waluś B, Malecki MT, Sanak M, Whittall R, Li KW, Futema M, Humphries SE.

Metabolism. 2016 Mar;65(3):48-53. doi: 10.1016/j.metabol.2015.10.018. Epub 2015 Nov 10.

PubMed [citation]

PMID:: 26892515
PMCID:: PMC4766367

Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography.

Li JJ, Li S, Zhu CG, Wu NQ, Zhang Y, Guo YL, Gao Y, Li XL, Qing P, Cui CJ, Xu RX, Jiang ZW, Sun J, Liu G, Dong Q.

Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):570-579. doi: 10.1161/ATVBAHA.116.308456. Epub 2016 Dec 8.

PubMed [citation]

PMID:: 27932355

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443108.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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. ClinVar contains an entry for this variant (Variation ID: 252176). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 26892515, 27932355, 30526649). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 676 of the LDLR protein (p.Gly676Arg). This variant disrupts the p.Gly676 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12417285, 31491741; 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 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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