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NM_000527.5(LDLR):c.388T>A (p.Ser130Thr) AND Hypercholesterolemia, familial, 1

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jun 26, 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:
RCV000238545.3

Allele description [Variation Report for NM_000527.5(LDLR):c.388T>A (p.Ser130Thr)]

NM_000527.5(LDLR):c.388T>A (p.Ser130Thr)

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.388T>A (p.Ser130Thr)
HGVS:
  • NC_000019.10:g.11105294T>A
  • NG_009060.1:g.20914T>A
  • NM_000527.5:c.388T>AMANE SELECT
  • NM_001195798.2:c.388T>A
  • NM_001195799.2:c.265T>A
  • NM_001195800.2:c.314-2098T>A
  • NM_001195803.2:c.314-1271T>A
  • NP_000518.1:p.Ser130Thr
  • NP_001182727.1:p.Ser130Thr
  • NP_001182728.1:p.Ser89Thr
  • LRG_274t1:c.388T>A
  • LRG_274:g.20914T>A
  • NC_000019.9:g.11215970T>A
  • NM_000527.4:c.388T>A
  • c.388T>A
Protein change:
S130T
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000936; dbSNP: rs879254508
NCBI 1000 Genomes Browser:
rs879254508
Molecular consequence:
  • NM_001195800.2:c.314-2098T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1271T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.388T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.388T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.265T>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hypercholesterolemia, familial, 1
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000294678LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Likely benign
(Mar 25, 2016) 		germlineliterature only

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

Citation Link,

SCV004820159All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Jun 26, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedliterature only
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.

Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H.

Atherosclerosis. 2002 Dec;165(2):335-42. Erratum in: Atherosclerosis. 2004 Jun;174(2):399-400.

PubMed [citation]
PMID:
12417285

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

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294678.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004820159.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

This missense variant (also known as p.Ser109Thr in the mature protein) replaces serine with threonine at codon 130 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified 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
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 1, 2024