NM_000527.5(LDLR):c.1335C>A (p.Asp445Glu) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 18, 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:: RCV000237931.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1335C>A (p.Asp445Glu)]

NM_000527.5(LDLR):c.1335C>A (p.Asp445Glu)

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.1335C>A (p.Asp445Glu)

Other names:

FH Finn-8

HGVS:

NC_000019.10:g.11113426C>A
NG_009060.1:g.29046C>A
NM_000527.5:c.1335C>AMANE SELECT
NM_001195798.2:c.1335C>A
NM_001195799.2:c.1212C>A
NM_001195800.2:c.831C>A
NM_001195803.2:c.954C>A
NP_000518.1:p.Asp445Glu
NP_001182727.1:p.Asp445Glu
NP_001182728.1:p.Asp404Glu
NP_001182729.1:p.Asp277Glu
NP_001182732.1:p.Asp318Glu
LRG_274t1:c.1335C>A
LRG_274:g.29046C>A
NC_000019.9:g.11224102C>A
NM_000527.4:c.1335C>A
c.1335C>A

Protein change:

D277E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001400; dbSNP: rs749780672

NCBI 1000 Genomes Browser:

rs749780672

Molecular consequence:

NM_000527.5:c.1335C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1335C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1212C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.831C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.954C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295374	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 7573037, 15199436 Citation Link,
SCV004820301	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 18, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7573037, 15199436, 31587492, 33740630, 35474963, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295374

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV004820301

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 18, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	2	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene.

Koivisto UM, Viikari JS, Kontula K.

Am J Hum Genet. 1995 Oct;57(4):789-97.

PubMed [citation]

PMID:: 7573037
PMCID:: PMC1801494

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

See all PubMed Citations (6)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295374.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	PubMed (2)

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

From All of Us Research Program, National Institutes of Health, SCV004820301.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces aspartic acid with glutamic acid at codon 445 of the LDLR protein. This variant is also known as pAsp424Glu in the mature protein, and as FH-Finn-8 in the literature. This variant alters a conserved aspartic acid residue in the LDLR type B repeat 2 of the LDLR protein (a.a. 439 - 485), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. One functional study suggested this variant does not affect protein expression, folding, or intracellular trafficking (PMID: 31587492). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 7573037, 15199436, 33740630, 35474963; DOI: 10.1093/eurheartj/ehab724.2566). This variant has been identified in 4/251246 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		1	not provided	not provided	not provided

Last Updated: Sep 1, 2024

ClinVar

Relating variation to medicine