NM_000527.5(LDLR):c.508G>A (p.Asp170Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 13, 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:: RCV000211593.11

Allele description [Variation Report for NM_000527.5(LDLR):c.508G>A (p.Asp170Asn)]

NM_000527.5(LDLR):c.508G>A (p.Asp170Asn)

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.508G>A (p.Asp170Asn)

HGVS:

NC_000019.10:g.11105414G>A
NG_009060.1:g.21034G>A
NM_000527.5:c.508G>AMANE SELECT
NM_001195798.2:c.508G>A
NM_001195799.2:c.385G>A
NM_001195800.2:c.314-1978G>A
NM_001195803.2:c.314-1151G>A
NP_000518.1:p.Asp170Asn
NP_000518.1:p.Asp170Asn
NP_001182727.1:p.Asp170Asn
NP_001182728.1:p.Asp129Asn
LRG_274t1:c.508G>A
LRG_274:g.21034G>A
LRG_274p1:p.Asp170Asn
NC_000019.9:g.11216090G>A
NM_000527.4:c.508G>A

Protein change:

D129N

Links:

dbSNP: rs139089530

NCBI 1000 Genomes Browser:

rs139089530

Molecular consequence:

NM_001195800.2:c.314-1978G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1151G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.508G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.508G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.385G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

Clear Turn Off Turn On

Mus musculus melanocortin 3 receptor, mRNA (cDNA clone MGC:124211 IMAGE:40046711...
Mus musculus melanocortin 3 receptor, mRNA (cDNA clone MGC:124211 IMAGE:40046711), complete cds
gi|73909018|gb|BC103669.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000266315	Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT	criteria provided, single submitter (Mayo Cardiovascular Biomarkers Research Laboratory LDLR variant interpretation criteria, 2015)	Uncertain significance (Aug 31, 2016)	germline	research	PubMed (1) [See all records that cite this PMID] Kullo Lab Assertion Criteria_01072016.pdf, Citation Link,
SCV000268567	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Uncertain significance (Oct 7, 2011)	germline	clinical testing
SCV000606140	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004820174	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing, research
White	germline	no	not provided	not provided	not provided	1013	not provided	research

Citations

PubMed

Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals.

Safarova MS, Klee EW, Baudhuin LM, Winkler EM, Kluge ML, Bielinski SJ, Olson JE, Kullo IJ.

Eur J Hum Genet. 2017 Apr;25(4):410-415. doi: 10.1038/ejhg.2016.193. Epub 2017 Feb 1.

PubMed [citation]

PMID:: 28145427
PMCID:: PMC5386413

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 Cardiovascular Biomarker Research Laboratory, Mayo Clinic - RIGHT, SCV000266315.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	not provided	not provided	not provided	research	PubMed (1)

Description

MAF =<0.3%, likely pathogenic based on the integrative in-silico score; LDL-C >=160 mg/dL

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	1013	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268567.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606140.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004820174.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant (also known as p.Asp149Asn in the mature protein) replaces aspartic acid with asparagine at codon 170 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 been identified in 3/251270 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Sep 1, 2024

ClinVar

Relating variation to medicine