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NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) AND Familial hypercholesterolemia

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Oct 10, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001377111.7

Allele description [Variation Report for NM_000527.5(LDLR):c.139G>A (p.Asp47Asn)]

NM_000527.5(LDLR):c.139G>A (p.Asp47Asn)

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.139G>A (p.Asp47Asn)
Other names:
FH Hyogo; NM_000527.5(LDLR):c.139G>A
HGVS:
  • NC_000019.10:g.11100294G>A
  • NG_009060.1:g.15914G>A
  • NM_000527.5:c.139G>AMANE SELECT
  • NM_001195798.2:c.139G>A
  • NM_001195799.2:c.139G>A
  • NM_001195800.2:c.139G>A
  • NM_001195803.2:c.139G>A
  • NP_000518.1:p.Asp47Asn
  • NP_000518.1:p.Asp47Asn
  • NP_001182727.1:p.Asp47Asn
  • NP_001182728.1:p.Asp47Asn
  • NP_001182729.1:p.Asp47Asn
  • NP_001182732.1:p.Asp47Asn
  • LRG_274t1:c.139G>A
  • LRG_274:g.15914G>A
  • LRG_274p1:p.Asp47Asn
  • NC_000019.9:g.11210970G>A
  • NM_000527.4:c.139G>A
  • c.139G>A
Protein change:
D47N
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000383;
Molecular consequence:
  • NM_000527.5:c.139G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.139G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.139G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.139G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.139G>A - 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
SCV001574347Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 10, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004358467Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jun 13, 2023) 		germlineclinical testing

PubMed (12)
[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

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

Territoriality and personal space.

Stillman MJ.

Am J Nurs. 1978 Oct;78(10):1670-2. No abstract available.

PubMed [citation]
PMID:
251034
See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001574347.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 47 of the LDLR protein (p.Asp47Asn). This variant is present in population databases (rs778284147, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 11857755, 18718593, 29399563, 33547002; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as D26N. ClinVar contains an entry for this variant (Variation ID: 251034). 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. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 30413722). For these reasons, this variant has been classified as Pathogenic.

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

From Color Diagnostics, LLC DBA Color Health, SCV004358467.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This missense variant (also known as p.Asp26Asn in the mature protein, and as FH Hyogo) replaces aspartic acid with asparagine in the first LDLR-A repeat in codon 47 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). A functional study reported that this variant does not cause a defect in LDLR expression and function (PMID: 30413722). This LDLR variant has been reported in over 15 heterozygous individuals affected with familial hypercholesterolemia (PMID 11313767, 11857755, 18718593, 29399563, 32331935, 33547002, 33533259, 35319679, 35929461; communication with an external laboratory; ClinVar variation ID: 251034). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 35319679). It has been shown that this variant segregates with disease in 6 affected individuals from two unrelated families (communication with an external laboratory; ClinVar variation ID: 251034); some individuals carrying this variant did not show elevated cholesterol levels, reflecting incomplete penetrance. This variant has been identified in 4/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024