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NM_000527.5(LDLR):c.1177A>G (p.Lys393Glu) AND Familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 3, 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:
RCV003741305.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1177A>G (p.Lys393Glu)]

NM_000527.5(LDLR):c.1177A>G (p.Lys393Glu)

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.1177A>G (p.Lys393Glu)
HGVS:
  • NC_000019.10:g.11111630A>G
  • NG_009060.1:g.27250A>G
  • NM_000527.5:c.1177A>GMANE SELECT
  • NM_001195798.2:c.1177A>G
  • NM_001195799.2:c.1054A>G
  • NM_001195800.2:c.673A>G
  • NM_001195803.2:c.796A>G
  • NP_000518.1:p.Lys393Glu
  • NP_000518.1:p.Lys393Glu
  • NP_001182727.1:p.Lys393Glu
  • NP_001182728.1:p.Lys352Glu
  • NP_001182729.1:p.Lys225Glu
  • NP_001182732.1:p.Lys266Glu
  • LRG_274t1:c.1177A>G
  • LRG_274:g.27250A>G
  • LRG_274p1:p.Lys393Glu
  • NC_000019.9:g.11222306A>G
  • NM_000527.4:c.1177A>G
Protein change:
K225E
Molecular consequence:
  • NM_000527.5:c.1177A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1177A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1054A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.673A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.796A>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004375138Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Mar 3, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia.

Rieck L, Bardey F, Grenkowitz T, Bertram L, Helmuth J, Mischung C, Spranger J, Steinhagen-Thiessen E, Bobbert T, Kassner U, Demuth I.

Clin Genet. 2020 Nov;98(5):457-467. doi: 10.1111/cge.13826. Epub 2020 Sep 2.

PubMed [citation]
PMID:
32770674

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, SCV004375138.1

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

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 sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 393 of the LDLR protein (p.Lys393Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 32770674; Invitae). ClinVar contains an entry for this variant (Variation ID: 1740990). 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 disrupts the p.Lys393 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue.

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

Last Updated: Sep 29, 2024