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NM_000527.5(LDLR):c.2119G>A (p.Asp707Asn) AND Hypercholesterolemia, familial, 1

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 1, 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:
RCV000238203.3

Allele description [Variation Report for NM_000527.5(LDLR):c.2119G>A (p.Asp707Asn)]

NM_000527.5(LDLR):c.2119G>A (p.Asp707Asn)

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.2119G>A (p.Asp707Asn)
HGVS:
  • NC_000019.10:g.11120501G>A
  • NG_009060.1:g.36121G>A
  • NM_000527.5:c.2119G>AMANE SELECT
  • NM_001195798.2:c.2119G>A
  • NM_001195799.2:c.1996G>A
  • NM_001195800.2:c.1615G>A
  • NM_001195803.2:c.1606+268G>A
  • NP_000518.1:p.Asp707Asn
  • NP_001182727.1:p.Asp707Asn
  • NP_001182728.1:p.Asp666Asn
  • NP_001182729.1:p.Asp539Asn
  • LRG_274t1:c.2119G>A
  • LRG_274:g.36121G>A
  • NC_000019.9:g.11231177G>A
  • NM_000527.4:c.2119G>A
  • c.2119G>A
Protein change:
D539N
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000281; dbSNP: rs879255142
NCBI 1000 Genomes Browser:
rs879255142
Molecular consequence:
  • NM_001195803.2:c.1606+268G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.2119G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2119G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1996G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1615G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
4

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
SCV000295880LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

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

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

Citation Link,

SCV004818500All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 1, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedliterature only
not providedgermlineunknown4not providednot provided108544not providedclinical testing

Citations

PubMed

Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment.

Usifo E, Leigh SE, Whittall RA, Lench N, Taylor A, Yeats C, Orengo CA, Martin AC, Celli J, Humphries SE.

Ann Hum Genet. 2012 Sep;76(5):387-401. doi: 10.1111/j.1469-1809.2012.00724.x.

PubMed [citation]
PMID:
22881376

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, SCV000295880.2

#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, SCV004818500.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (2)

Description

This missense variant (also known as p.Asp686Asn in the mature protein) replaces aspartic acid with asparagine at codon 707 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 22881376). This variant has been identified in 1/250770 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
1germlineunknown108544not providednot provided4not providednot providednot provided

Last Updated: Sep 29, 2024