NM_000527.5(LDLR):c.2448G>C (p.Lys816Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Apr 28, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000508976.6

Allele description [Variation Report for NM_000527.5(LDLR):c.2448G>C (p.Lys816Asn)]

NM_000527.5(LDLR):c.2448G>C (p.Lys816Asn)

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.2448G>C (p.Lys816Asn)

Other names:

NM_000527.5(LDLR):c.2448G>C; p.Lys816Asn

HGVS:

NC_000019.10:g.11129571G>C
NG_009060.1:g.45191G>C
NM_000527.5:c.2448G>CMANE SELECT
NM_001195798.2:c.2448G>C
NM_001195799.2:c.2325G>C
NM_001195800.2:c.1944G>C
NM_001195803.2:c.1914G>C
NP_000518.1:p.Lys816Asn
NP_000518.1:p.Lys816Asn
NP_001182727.1:p.Lys816Asn
NP_001182728.1:p.Lys775Asn
NP_001182729.1:p.Lys648Asn
NP_001182732.1:p.Lys638Asn
LRG_274t1:c.2448G>C
LRG_274:g.45191G>C
LRG_274p1:p.Lys816Asn
NC_000019.9:g.11240247G>C
NC_000019.9:g.11240247G>C
NM_000527.4:c.2448G>C

Protein change:

K638N

Links:

dbSNP: rs1399689294

NCBI 1000 Genomes Browser:

rs1399689294

Molecular consequence:

NM_000527.5:c.2448G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2448G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2325G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1944G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1914G>C - 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

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RecName: Full=Glycine N-acyltransferase-like protein 1; AltName: Full=Acyl-CoA:g...
RecName: Full=Glycine N-acyltransferase-like protein 1; AltName: Full=Acyl-CoA:glycine N-acyltransferase-like protein 1; AltName: Full=Glutamine N-acyltransferase
gi|74731045|sp|Q969I3.1|GLYL1_HUMAN

Protein
ACOX3 [Gorilla gorilla gorilla]
ACOX3 [Gorilla gorilla gorilla]
Gene ID:101152360

Gene
Profile neighbors for GEO Profiles (Select 75738) (200)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 70094) (19)
GEO Profiles
Bone marrow stromal cell lines
Bone marrow stromal cell lines
Accession: GDS12

GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000606655	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607708	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000748158	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004022405	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Apr 28, 2023)	germline	curation	Citation Link,
SCV004843592	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

Variant present in the database from Uruguay: SCV000748158

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research, curation

Citations

PubMed

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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606655.1

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607708.1

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

#	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 Iberoamerican FH Network, SCV000748158.1

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

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022405.1

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

Description

NM_000527.4(LDLR): c.2448G>C (p.Lys816Asn) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: PopMax MAF = 0.00006482 (0.007%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). . BP4: REVEL = 0.5. It is not below 0.5, splicing evaluation is needed. Functional data on splicing not available. A) variant is not on limits B) Variant does not create GT or AG Variant is not predicted to affect splicing.

#	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, SCV004843592.1

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

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

Last Updated: Sep 1, 2024

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