NM_000527.5(LDLR):c.169G>A (p.Asp57Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 29, 2022
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:: RCV000238214.11

Allele description [Variation Report for NM_000527.5(LDLR):c.169G>A (p.Asp57Asn)]

NM_000527.5(LDLR):c.169G>A (p.Asp57Asn)

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.169G>A (p.Asp57Asn)

Other names:

NM_000527.5(LDLR):c.169G>A; p.Asp57Asn

HGVS:

NC_000019.10:g.11100324G>A
NG_009060.1:g.15944G>A
NM_000527.5:c.169G>AMANE SELECT
NM_001195798.2:c.169G>A
NM_001195799.2:c.169G>A
NM_001195800.2:c.169G>A
NM_001195803.2:c.169G>A
NP_000518.1:p.Asp57Asn
NP_000518.1:p.Asp57Asn
NP_001182727.1:p.Asp57Asn
NP_001182728.1:p.Asp57Asn
NP_001182729.1:p.Asp57Asn
NP_001182732.1:p.Asp57Asn
LRG_274t1:c.169G>A
LRG_274:g.15944G>A
LRG_274p1:p.Asp57Asn
NC_000019.9:g.11211000G>A
NM_000527.4:c.169G>A
c.169G>A

Protein change:

D57N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000022; dbSNP: rs879254420

NCBI 1000 Genomes Browser:

rs879254420

Molecular consequence:

NM_000527.5:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001281757	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002817135	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Aug 29, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001281757

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

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

Citation Link,

SCV002817135

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Aug 29, 2022)

germline

curation

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]

PMID:: 20145306

Details of each submission

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606030.1

#	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 Illumina Laboratory Services, Illumina, SCV001281757.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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, SCV002817135.1

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

Description

The NM_000527.5(LDLR):c.169G>A (p.Asp57Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 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: This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met. PP3: REVEL= 0.791. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 1 case fulfilling WHO criteria published in PMID: 20145306 (Chmara et al., 2010). So PP4 is met.

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000606030	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None	Pathogenic	germline	research

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000606030

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

Pathogenic

germline

research

Last Updated: Sep 1, 2024

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