NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Jul 11, 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:: RCV000211642.10

Allele description [Variation Report for NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)]

NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)

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.938G>A (p.Cys313Tyr)

HGVS:

NC_000019.10:g.11107512G>A
NG_009060.1:g.23132G>A
NM_000527.5:c.938G>AMANE SELECT
NM_001195798.2:c.938G>A
NM_001195799.2:c.815G>A
NM_001195800.2:c.434G>A
NM_001195803.2:c.557G>A
NP_000518.1:p.Cys313Tyr
NP_000518.1:p.Cys313Tyr
NP_001182727.1:p.Cys313Tyr
NP_001182728.1:p.Cys272Tyr
NP_001182729.1:p.Cys145Tyr
NP_001182732.1:p.Cys186Tyr
LRG_274t1:c.938G>A
LRG_274:g.23132G>A
LRG_274p1:p.Cys313Tyr
NC_000019.9:g.11218188G>A
NM_000527.4:c.938G>A
P01130:p.Cys313Tyr
c.938G>A

Protein change:

C145Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001871; UniProtKB: P01130#VAR_005358; dbSNP: rs875989911

NCBI 1000 Genomes Browser:

rs875989911

Molecular consequence:

NM_000527.5:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.815G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.434G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.557G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268591	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Mar 18, 2010)	germline	clinical testing
SCV000295072	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 9259195, 11810272, 11857755 Citation Link,
SCV000606274	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607528	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000840001	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 25, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004822561	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jul 11, 2023)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 7548065, 7603991, 7979249, 9259195, 9698020, 11040093, 11810272, 11857755, 17094996, 21382890, 22883975, 23833242, 27680772, 33269076, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	7	not provided	not provided	6	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain.

Bieri S, Djordjevic JT, Daly NL, Smith R, Kroon PA.

Biochemistry. 1995 Oct 10;34(40):13059-65.

PubMed [citation]

PMID:: 7548065

Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.

Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R.

Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6334-8.

PubMed [citation]

PMID:: 7603991
PMCID:: PMC41512

See all PubMed Citations (15)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268591.1

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

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

From LDLR-LOVD, British Heart Foundation, SCV000295072.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (3)
2	not provided	1	not provided	not provided	literature only	PubMed (3)
3	not provided	1	not provided	not provided	literature only	PubMed (3)
4	not provided	1	not provided	not provided	literature only	PubMed (3)
5	not provided	1	not provided	not provided	literature only	PubMed (3)
6	not provided	1	not provided	not provided	literature only	PubMed (3)

#	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
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606274.1

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607528.1

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

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840001.1

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

Description

This c.938G>A (p.Cys313Tyr) variant in the LDLR gene has been reported in multiple familial hypercholesterolemia patients [PMID: 9259195, 11857755, 11810272] but not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. Multiple in silico predictions suggest this cysteine to tyrosine is deleterious. Multiple variants causing cysteine at amino acid position 313 change to other amino acids have been reported as disease-causing in literature [PMID: 19318025, 15823288, 11257257]. Based upon above evidences, c.938G>A (p.Cys313Tyr) variant in the LDLR gene is classified as likely pathogenic.

#	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, SCV004822561.1

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

Description

The c.938G>A (p.Cys313Tyr) variant of the LDLR gene has been identified in heterozygous status in multiple (>10) unrelated individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 9259195, 9698020, 11040093, 11810272, 11857755, 27680772, 33269076, 23833242, 22883975, 17094996). This variant has also been identified in compound heterozygous status in two individuals with FH (PMID: 21382890). In-silico computational prediction tools suggest that the p.Cys313Tyr variant may have deleterious effect on protein function (REVEL score: 0.979). This variant affects one of the sixty highly conserved cysteine residues located within an LDLR class A or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 226339). Other amino acid substitutions at the same codon (p.Cys313Gly, p.Cys313Trp) have been classified as likely pathogenic by several ClinVar submitters (ClinVar ID: 251538, 251540). Therefore, the c.938G>A (p.Cys313Tyr) variant in the LDLR gene 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: Apr 20, 2024

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