NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Apr 3, 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:: RCV000238401.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys)]

NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys)

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.1394A>G (p.Tyr465Cys)

HGVS:

NC_000019.10:g.11113570A>G
NG_009060.1:g.29190A>G
NM_000527.5:c.1394A>GMANE SELECT
NM_001195798.2:c.1394A>G
NM_001195799.2:c.1271A>G
NM_001195800.2:c.890A>G
NM_001195803.2:c.1013A>G
NP_000518.1:p.Tyr465Cys
NP_000518.1:p.Tyr465Cys
NP_001182727.1:p.Tyr465Cys
NP_001182728.1:p.Tyr424Cys
NP_001182729.1:p.Tyr297Cys
NP_001182732.1:p.Tyr338Cys
LRG_274t1:c.1394A>G
LRG_274:g.29190A>G
LRG_274p1:p.Tyr465Cys
NC_000019.9:g.11224246A>G
NM_000527.4:c.1394A>G
c.1394A>G

Protein change:

Y297C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001421; dbSNP: rs879254889

NCBI 1000 Genomes Browser:

rs879254889

Molecular consequence:

NM_000527.5:c.1394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1271A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.890A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1013A>G - 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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Activating transcription factor 4 (tax-responsive enhancer element B67) [Homo sa...
Activating transcription factor 4 (tax-responsive enhancer element B67) [Homo sapiens]
gi|16877178|gb|AAH16855.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295411	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000540816	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)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 22698793
SCV000606414	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004822962	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22698793, 33740630, 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, research
Caucasian	inherited	yes	5	3	not provided	3964	yes	clinical testing

Citations

PubMed

The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.

Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2012 Aug;223(2):401-8. doi: 10.1016/j.atherosclerosis.2012.05.014. Epub 2012 May 23.

PubMed [citation]

PMID:: 22698793

Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020.

Leren TP, Bogsrud MP.

Atherosclerosis. 2021 Apr;322:61-66. doi: 10.1016/j.atherosclerosis.2021.02.022. Epub 2021 Feb 23.

PubMed [citation]

PMID:: 33740630

See all PubMed Citations (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295411.2

#	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, SCV000540816.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	5	not provided	yes	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3964	Whole blood	not provided		5	not provided	3	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606414.1

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

From All of Us Research Program, National Institutes of Health, SCV004822962.1

#	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.Tyr444Cys in the mature protein) replaces tyrosine with cysteine at codon 465 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 individuals affected with familial hypercholesterolemia (PMID: 22698793, 33740630). This variant has not been identified 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 29, 2024

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