NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Jun 7, 2021
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:: RCV000237660.9

Allele description [Variation Report for NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr)]

NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr)

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.268G>T (p.Asp90Tyr)

Other names:

NM_000527.5(LDLR):c.268G>T

HGVS:

NC_000019.10:g.11102741G>T
NG_009060.1:g.18361G>T
NM_000527.5:c.268G>TMANE SELECT
NM_001195798.2:c.268G>T
NM_001195799.2:c.190+2396G>T
NM_001195800.2:c.268G>T
NM_001195803.2:c.268G>T
NP_000518.1:p.Asp90Tyr
NP_000518.1:p.Asp90Tyr
NP_001182727.1:p.Asp90Tyr
NP_001182729.1:p.Asp90Tyr
NP_001182732.1:p.Asp90Tyr
LRG_274t1:c.268G>T
LRG_274:g.18361G>T
LRG_274p1:p.Asp90Tyr
NC_000019.9:g.11213417G>T
NM_000527.4:c.268G>T
P01130:p.Asp90Tyr
c.268G>T

Protein change:

D90Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001675; UniProtKB: P01130#VAR_005312; dbSNP: rs749038326

NCBI 1000 Genomes Browser:

rs749038326

Molecular consequence:

NM_001195799.2:c.190+2396G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.268G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.268G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.268G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.268G>T - 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
SCV000294570	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000540722	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation See additional submitters Centre of Molecular Biology and Gene Therapy, University Hospital Brno	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 5, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001960913	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Likely pathogenic (Jun 7, 2021)	germline	curation	Citation Link,
SCV004830222	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jun 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8347689, 34456200, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, curation
Caucasian	unknown	yes	1	1	not provided	3964	yes	clinical testing

Citations

PubMed

Identification of two new LDL-receptor mutations causing homozygous familial hypercholesterolemia in a South African of Indian origin.

Rubinsztein DC, Jialal I, Leitersdorf E, Coetzee GA, van der Westhuyzen DR.

Biochim Biophys Acta. 1993 Aug 4;1182(1):75-82.

PubMed [citation]

PMID:: 8347689

Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020.

Kim H, Lee CJ, Kim SH, Kim JY, Choi SH, Kang HJ, Park KS, Cho BR, Kim BJ, Sung KC, Jeong IK, Jeong JO, Bae JW, Park JM, Lee Y, Jeong I, Han H, Lee JH, Lee SH.

J Atheroscler Thromb. 2022 Aug 1;29(8):1176-1187. doi: 10.5551/jat.63062. Epub 2021 Aug 30.

PubMed [citation]

PMID:: 34456200
PMCID:: PMC9371750

See all PubMed Citations (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294570.2

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

#	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

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540722.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	3964	Whole blood	not provided		1	not provided	1	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960913.1

#	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.268G>T (p.Asp90Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_Strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PM5 - Four more missense variants described in same codon, 3 variants classified as Pathogenic, so PM5 is Met. PP3 - REVEL = 0.958. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2. Identified in 1 index case who fulfills Simon-Broome criteria from Center of molecular biology and gene therapy.

#	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 All of Us Research Program, National Institutes of Health, SCV004830222.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant (also known as p.Asp69Tyr in the mature protein) replaces aspartic acid with tyrosine at codon 90 in the second LDLR type A of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 34456200). This variant has also been reported in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 8347689). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon (p.Asp90Asn, p.Asp90Gly, p.Asp90Glu, p.Asp90Ala), are well documented pathogenic mutations (ClinVar variation IDs: 215505, 226313, 251107, 440555), indicating that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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 29, 2024

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