NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) AND Homozygous familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 15, 2020
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:: RCV000844745.15

Allele description [Variation Report for NM_000527.5(LDLR):c.798T>A (p.Asp266Glu)]

NM_000527.5(LDLR):c.798T>A (p.Asp266Glu)

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.798T>A (p.Asp266Glu)

Other names:

NP_000518.1:p.D266E; NM_000527.5(LDLR):c.798T>A

HGVS:

NC_000019.10:g.11106668T>A
NG_009060.1:g.22288T>A
NM_000527.5:c.798T>AMANE SELECT
NM_001195798.2:c.798T>A
NM_001195799.2:c.675T>A
NM_001195800.2:c.314-724T>A
NM_001195803.2:c.417T>A
NP_000518.1:p.Asp266Glu
NP_000518.1:p.Asp266Glu
NP_001182727.1:p.Asp266Glu
NP_001182728.1:p.Asp225Glu
NP_001182732.1:p.Asp139Glu
LRG_274t1:c.798T>A
LRG_274:g.22288T>A
LRG_274p1:p.Asp266Glu
NC_000019.9:g.11217344T>A
NM_000527.2:c.798T>A
NM_000527.4:c.798T>A
P01130:p.Asp266Glu
c.798T>A

Protein change:

D139E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000117; UniProtKB: P01130#VAR_005347; dbSNP: rs139043155

NCBI 1000 Genomes Browser:

rs139043155

Molecular consequence:

NM_001195800.2:c.314-724T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.798T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.798T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.675T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.417T>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence - Comment(s)

Observations:

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000711397	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Nov 15, 2020)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 23375686, 21310417, 25637381, 1301956, 26036859, 20145306, 25487149, 26892515, 10657581, 16542394, 20663204, 11810272, 11196104, 22698793, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000711397

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Nov 15, 2020)

germline

clinical testing

PubMed (15)
[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	22	22	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia.

Dušková L, Kopečková L, Jansová E, Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2011 May;216(1):139-45. doi: 10.1016/j.atherosclerosis.2011.01.023. Epub 2011 Jan 21.

PubMed [citation]

PMID:: 21310417

See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711397.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	22	not provided	not provided	clinical testing	PubMed (15)

Description

The p.Asp266Glu variant (also described as p.Asp245Glu in the literature) has been reported in over 100 individuals with familial hypercholesterolemia (FH; Bertolini 2013 PMID: 23375686, BrÃ¦nne 2015 PMID: 26036859, Brusgaard 2006 PMID: 16542394, Chmara 2010 PMID: 20145306, Do 2015 PMID: 25487149, Fouchier 2001 PMID: 11810272, Hobbs 1992 PMID: 1301956, Schmidt 2000 PMID: 10657581, Sharifi 2016 PMID: 26892515, TichÃ½ 2012 PMID: 22698793, Weiss 2000 PMID: 11196104) and reportedly segregated with disease in numerous affected relatives from multiple families (Clinvar, Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation SCV000540759.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161287) and has been identified in 0.008% (10/129194) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Asp266Glu variant may impact protein function, resulting in 15-30% LDL receptor activity (Hobbs 1992 PMID: 1301956). Computational prediction tools and conservation analysis suggest that the p.Asp266Glu variant may impact the protein. Another likely pathogenic missense change at the same position (p.Asp266Tyr) has been reported in association to FH (reported as p.Asp245Tyr, Weiss 2000 PMID: 11196104). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM5_Supporting, PM2_Supporting , PP3, PS3_supporting.

#	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		22	not provided	22	not provided

Last Updated: Nov 3, 2024

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