NM_000527.5(LDLR):c.1335C>G (p.Asp445Glu) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 1, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000819259.5

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

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

HGVS:

NC_000019.10:g.11113426C>G
NG_009060.1:g.29046C>G
NM_000527.5:c.1335C>GMANE SELECT
NM_001195798.2:c.1335C>G
NM_001195799.2:c.1212C>G
NM_001195800.2:c.831C>G
NM_001195803.2:c.954C>G
NP_000518.1:p.Asp445Glu
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>G
LRG_274:g.29046C>G
LRG_274p1:p.Asp445Glu
NC_000019.9:g.11224102C>G
NM_000527.4:c.1335C>G

Protein change:

D277E

Links:

dbSNP: rs749780672

NCBI 1000 Genomes Browser:

rs749780672

Molecular consequence:

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

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000959909	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7573037, 15199436, 31587492, 28492532
SCV002086417	Natera, Inc.	no assertion criteria provided	Uncertain significance (Aug 24, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000959909

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002086417

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Aug 24, 2020)

germline

clinical testing

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

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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000959909.2

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

Description

This sequence change replaces aspartic acid with glutamic acid at codon 445 of the LDLR protein (p.Asp445Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 7573037, 15199436). This variant is also known as p.Asp242Glu and FH-Fin-8. ClinVar contains an entry for this variant (Variation ID: 661768). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 31587492). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002086417.1

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

Last Updated: Sep 29, 2024

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