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NM_000527.5(LDLR):c.1318A>G (p.Arg440Gly) AND Familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 2, 2021
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:
RCV001857826.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1318A>G (p.Arg440Gly)]

NM_000527.5(LDLR):c.1318A>G (p.Arg440Gly)

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.1318A>G (p.Arg440Gly)
HGVS:
  • NC_000019.10:g.11113409A>G
  • NG_009060.1:g.29029A>G
  • NM_000527.5:c.1318A>GMANE SELECT
  • NM_001195798.2:c.1318A>G
  • NM_001195799.2:c.1195A>G
  • NM_001195800.2:c.814A>G
  • NM_001195803.2:c.937A>G
  • NP_000518.1:p.Arg440Gly
  • NP_001182727.1:p.Arg440Gly
  • NP_001182728.1:p.Arg399Gly
  • NP_001182729.1:p.Arg272Gly
  • NP_001182732.1:p.Arg313Gly
  • LRG_274:g.29029A>G
  • NC_000019.9:g.11224085A>G
  • c.1318A>G
Protein change:
R272G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000968; dbSNP: rs879254861
NCBI 1000 Genomes Browser:
rs879254861
Molecular consequence:
  • NM_000527.5:c.1318A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1318A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1195A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.814A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.937A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002300720Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Dec 2, 2021)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Comparison of SSCP and DHPLC for the detection of LDLR mutations in a New Zealand cohort.

Bunn CF, Lintott CJ, Scott RS, George PM.

Hum Mutat. 2002 Mar;19(3):311.

PubMed [citation]
PMID:
11857755

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002300720.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11857755; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 440 of the LDLR protein (p.Arg440Gly). This variant is also known as R419G. 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. 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: 251781).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024