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NM_000527.5(LDLR):c.1438G>T (p.Ala480Ser) AND Familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 29, 2022
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:
RCV002643933.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1438G>T (p.Ala480Ser)]

NM_000527.5(LDLR):c.1438G>T (p.Ala480Ser)

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.1438G>T (p.Ala480Ser)
HGVS:
  • NC_000019.10:g.11113614G>T
  • NG_009060.1:g.29234G>T
  • NM_000527.5:c.1438G>TMANE SELECT
  • NM_001195798.2:c.1438G>T
  • NM_001195799.2:c.1315G>T
  • NM_001195800.2:c.934G>T
  • NM_001195803.2:c.1057G>T
  • NP_000518.1:p.Ala480Ser
  • NP_000518.1:p.Ala480Ser
  • NP_001182727.1:p.Ala480Ser
  • NP_001182728.1:p.Ala439Ser
  • NP_001182729.1:p.Ala312Ser
  • NP_001182732.1:p.Ala353Ser
  • LRG_274t1:c.1438G>T
  • LRG_274:g.29234G>T
  • LRG_274p1:p.Ala480Ser
  • NC_000019.9:g.11224290G>T
  • NM_000527.4:c.1438G>T
Protein change:
A312S
Molecular consequence:
  • NM_000527.5:c.1438G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1438G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1315G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.934G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1057G>T - 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
SCV003512063Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Nov 29, 2022) 		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

Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C-->T mutation of low-density lipoprotein receptor gene.

Lin J, Wang LY, Liu S, Xia JH, Yong Q, Du LP, Pan XD, Xue H, Chen BS, Jiang ZS.

Chin Med J (Engl). 2008 May 5;121(9):776-81.

PubMed [citation]
PMID:
18701038

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, SCV003512063.2

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

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. 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 variant disrupts the p.Ala480 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18701038; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 480 of the LDLR protein (p.Ala480Ser).

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

Last Updated: Sep 29, 2024