NM_000527.5(LDLR):c.1019G>A (p.Cys340Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Nov 14, 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:: RCV000237709.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1019G>A (p.Cys340Tyr)]

NM_000527.5(LDLR):c.1019G>A (p.Cys340Tyr)

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.1019G>A (p.Cys340Tyr)

HGVS:

NC_000019.10:g.11110730G>A
NG_009060.1:g.26350G>A
NM_000527.5:c.1019G>AMANE SELECT
NM_001195798.2:c.1019G>A
NM_001195799.2:c.896G>A
NM_001195800.2:c.515G>A
NM_001195803.2:c.638G>A
NP_000518.1:p.Cys340Tyr
NP_000518.1:p.Cys340Tyr
NP_001182727.1:p.Cys340Tyr
NP_001182728.1:p.Cys299Tyr
NP_001182729.1:p.Cys172Tyr
NP_001182732.1:p.Cys213Tyr
LRG_274t1:c.1019G>A
LRG_274:g.26350G>A
LRG_274p1:p.Cys340Tyr
NC_000019.9:g.11221406G>A
NM_000527.4:c.1019G>A
c.1019G>A

Protein change:

C172Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000837; dbSNP: rs755757866

NCBI 1000 Genomes Browser:

rs755757866

Molecular consequence:

NM_000527.5:c.1019G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1019G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.896G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.515G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.638G>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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NADH dehydrogenase subunit 6 (mitochondrion) [Propithecus edwardsi]
NADH dehydrogenase subunit 6 (mitochondrion) [Propithecus edwardsi]
gi|2267398446|gb|UTE81783.1|

Protein
von Willebrand factor C domain-containing protein 2-like isoform 1 precursor [Mu...
von Willebrand factor C domain-containing protein 2-like isoform 1 precursor [Mus musculus]
gi|70887782|ref|NP_796138.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295143	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,
SCV000540782	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]
SCV004820252	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7548065, 7603991, 7979249, 15241806, 27824480, 30592178, 33391333, 34834584, 35560019, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295143

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,

SCV000540782

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 5, 2016)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004820252

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 14, 2023)

germline

clinical testing

PubMed (10)
[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	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	unknown	yes	1	1	not provided	3964	not provided	clinical testing

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 (10)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295143.2

#	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, SCV000540782.1

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

Description

Disrupt disulfide bridge between Cys340 and Cys352.

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607545.1

#	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 All of Us Research Program, National Institutes of Health, SCV004820252.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

The c.1019G>A (p.Cys340Tyr) variant in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in in at least ten unrelated individuals with Familial Hypercholesterolemia (FH) (PMID:34834584, 30592178, 27824480, 15241806, 35560019, 33391333). Another study reports that this variant has been identified in three Slovak probands with FH and three relatives, however the phenotype of the relatives are not clear (PMID: 27824480). This variant affects a cysteine residue located within an LDLRA 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). In-silico computational prediction tools suggest that the p.Cys340Tyr variant may have deleterious effect on the protein function (REVEL score: 0.923). 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: 251600). Therefore, the c.1019G>A (p.Cys340Tyr) 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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000607545	Fundacion Hipercolesterolemia Familiar - SAFEHEART	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000607545

Fundacion Hipercolesterolemia Familiar - SAFEHEART

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 1, 2016)

germline

research

PubMed (1)
[See all records that cite this PMID]

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine