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NM_000527.5(LDLR):c.1580T>C (p.Val527Ala) AND Familial hypercholesterolemia

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 11, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV001183446.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1580T>C (p.Val527Ala)]

NM_000527.5(LDLR):c.1580T>C (p.Val527Ala)

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.1580T>C (p.Val527Ala)
HGVS:
  • NC_000019.10:g.11113756T>C
  • NG_009060.1:g.29376T>C
  • NM_000527.5:c.1580T>CMANE SELECT
  • NM_001195798.2:c.1580T>C
  • NM_001195799.2:c.1457T>C
  • NM_001195800.2:c.1076T>C
  • NM_001195803.2:c.1199T>C
  • NP_000518.1:p.Val527Ala
  • NP_000518.1:p.Val527Ala
  • NP_001182727.1:p.Val527Ala
  • NP_001182728.1:p.Val486Ala
  • NP_001182729.1:p.Val359Ala
  • NP_001182732.1:p.Val400Ala
  • LRG_274t1:c.1580T>C
  • LRG_274:g.29376T>C
  • LRG_274p1:p.Val527Ala
  • NC_000019.9:g.11224432T>C
  • NM_000527.4:c.1580T>C
Protein change:
V359A
Links:
dbSNP: rs730882107
NCBI 1000 Genomes Browser:
rs730882107
Molecular consequence:
  • NM_000527.5:c.1580T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1580T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1457T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1076T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1199T>C - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)

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
SCV001349166Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 27, 2023)
germlineclinical testing

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

SCV004265387Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely benign
(Dec 11, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.

Thormaehlen AS, Schuberth C, Won HH, Blattmann P, Joggerst-Thomalla B, Theiss S, Asselta R, Duga S, Merlini PA, Ardissino D, Lander ES, Gabriel S, Rader DJ, Peloso GM, Pepperkok R, Kathiresan S, Runz H.

PLoS Genet. 2015 Feb;11(2):e1004855. doi: 10.1371/journal.pgen.1004855. Erratum in: PLoS Genet. 2015 Mar 17;11(3):e1005060. doi: 10.1371/journal.pgen.1005060.

PubMed [citation]
PMID:
25647241
PMCID:
PMC4409815

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001349166.4

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

Description

This missense variant (also known as p.Val506Ala in the mature protein) replaces valine with alanine at codon 527 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR protein function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has been identified in 19/251244 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004265387.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024