NM_000527.5(LDLR):c.1013G>A (p.Cys338Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Aug 28, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000238118.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1013G>A (p.Cys338Tyr)]

NM_000527.5(LDLR):c.1013G>A (p.Cys338Tyr)

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.1013G>A (p.Cys338Tyr)

HGVS:

NC_000019.10:g.11110724G>A
NG_009060.1:g.26344G>A
NM_000527.5:c.1013G>AMANE SELECT
NM_001195798.2:c.1013G>A
NM_001195799.2:c.890G>A
NM_001195800.2:c.509G>A
NM_001195803.2:c.632G>A
NP_000518.1:p.Cys338Tyr
NP_000518.1:p.Cys338Tyr
NP_001182727.1:p.Cys338Tyr
NP_001182728.1:p.Cys297Tyr
NP_001182729.1:p.Cys170Tyr
NP_001182732.1:p.Cys211Tyr
LRG_274t1:c.1013G>A
LRG_274:g.26344G>A
LRG_274p1:p.Cys338Tyr
NC_000019.9:g.11221400G>A
NM_000527.4:c.1013G>A
c.1013G>A

Protein change:

C170Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000620;

Molecular consequence:

NM_000527.5:c.1013G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1013G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.890G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.509G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.632G>A - 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

Recent activity

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F-box and leucine-rich protein 22 isoform 1 [Homo sapiens]
F-box and leucine-rich protein 22 isoform 1 [Homo sapiens]
gi|308044497|ref|NP_976307.2|

Protein
Saccharomyces cerevisiae S288C Srb7p (SRB7), partial mRNA
Saccharomyces cerevisiae S288C Srb7p (SRB7), partial mRNA
gi|398366468|ref|NM_001180616.3|

Nucleotide
NDR1/HIN1-like protein 6 isoform X1 [Cucurbita maxima]
NDR1/HIN1-like protein 6 isoform X1 [Cucurbita maxima]
gi|1281064380|ref|XP_022974636.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295138	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10924730, 21310417 Citation Link,
SCV000540781	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 (2) [See all records that cite these PMIDs] 25741868, 22698793
SCV000588538	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 10924730
SCV004101320	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (Aug 28, 2023)	unknown	clinical testing	Citation Link

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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	research
not provided	germline	yes	2	not provided	not provided	2	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	unknown	yes	1	1	not provided	3964	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295138.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	PubMed (2)

#	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
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540781.1

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

Description

Disrupt disulfide bridge between Cys325 and Cys338.

#	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 Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588538.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

"Assay description:Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 10924730]

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV004101320.1

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

Description

The LDLR c.1013G>A (p.Cys338Tyr) missense variant results in the substitution of cysteine at amino acid position 338 with tyrosine. This variant has been identified in individuals with a phenotype consistent with familial hypercholesterolemia, and has been shown to segregate with disease (PMID: 10924730; 34037665). A functional study conducted in patient cells demonstrated that this variant impacts protein function (PMID: 10924730). This variant affects one of 60 highly conserved cysteine residues that are critical for protein folding and function (PMID: 34906454). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1013G>A (p.Cys338Tyr) variant is classified as likely pathogenic for familial hypercholesterolemia.

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

Last Updated: Sep 29, 2024

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