NM_000527.5(LDLR):c.420G>T (p.Glu140Asp) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 16, 2019
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:: RCV001243628.8

Allele description [Variation Report for NM_000527.5(LDLR):c.420G>T (p.Glu140Asp)]

NM_000527.5(LDLR):c.420G>T (p.Glu140Asp)

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.420G>T (p.Glu140Asp)

HGVS:

NC_000019.10:g.11105326G>T
NG_009060.1:g.20946G>T
NM_000527.5:c.420G>TMANE SELECT
NM_001195798.2:c.420G>T
NM_001195799.2:c.297G>T
NM_001195800.2:c.314-2066G>T
NM_001195803.2:c.314-1239G>T
NP_000518.1:p.Glu140Asp
NP_000518.1:p.Glu140Asp
NP_001182727.1:p.Glu140Asp
NP_001182728.1:p.Glu99Asp
LRG_274t1:c.420G>T
LRG_274:g.20946G>T
LRG_274p1:p.Glu140Asp
NC_000019.9:g.11216002G>T
NM_000527.4:c.420G>T
c.420G>T

Protein change:

E140D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001732; dbSNP: rs879254520

NCBI 1000 Genomes Browser:

rs879254520

Molecular consequence:

NM_001195800.2:c.314-2066G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1239G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.420G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.420G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.297G>T - 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
SCV001416797	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 16, 2019)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1301956, 23375686, 21722902, 11668627, 15359125, 21310417, 17094996, 20145306, 11754108, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001416797

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 16, 2019)

germline

clinical testing

PubMed (10)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001416797.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu140 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 23375686, 21722902, 11668627, 15359125, 21310417). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 21310417, 17094996, 17094996, 20145306, 11754108). This variant is also described as Glu119Asp (E119D) in the literature. ClinVar contains an entry for this variant (Variation ID: 251217). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 140 of the LDLR protein (p.Glu140Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid.

#	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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