NM_000527.5(LDLR):c.809G>A (p.Cys270Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Jun 8, 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:: RCV000238081.5

Allele description [Variation Report for NM_000527.5(LDLR):c.809G>A (p.Cys270Tyr)]

NM_000527.5(LDLR):c.809G>A (p.Cys270Tyr)

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.809G>A (p.Cys270Tyr)

Other names:

FH Miami-2

HGVS:

NC_000019.10:g.11106679G>A
NG_009060.1:g.22299G>A
NM_000527.5:c.809G>AMANE SELECT
NM_001195798.2:c.809G>A
NM_001195799.2:c.686G>A
NM_001195800.2:c.314-713G>A
NM_001195803.2:c.428G>A
NP_000518.1:p.Cys270Tyr
NP_000518.1:p.Cys270Tyr
NP_001182727.1:p.Cys270Tyr
NP_001182728.1:p.Cys229Tyr
NP_001182732.1:p.Cys143Tyr
LRG_274t1:c.809G>A
LRG_274:g.22299G>A
LRG_274p1:p.Cys270Tyr
NC_000019.9:g.11217355G>A
NM_000527.4:c.809G>A
P01130:p.Cys270Tyr
c.809G>A

Protein change:

C143Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001843; UniProtKB: P01130#VAR_005348; dbSNP: rs879254683

NCBI 1000 Genomes Browser:

rs879254683

Molecular consequence:

NM_001195800.2:c.314-713G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.809G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.809G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.686G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.428G>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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HGSNAT [Rissa tridactyla]
HGSNAT [Rissa tridactyla]
Gene ID:128910104

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294986	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] 1301956, 7903864, 23375686 Citation Link,
SCV000606232	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004830243	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 (10) [See all records that cite these PMIDs] 1301956, 2088165, 6091915, 7903864, 15637307, 15952897, 23375686, 30270083, 34220717, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294986

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]

Citation Link,

SCV000606232

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

no assertion criteria provided

Pathogenic

germline

research

SCV004830243

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 (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	3	not provided	not provided	3	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.

Hobbs HH, Russell DW, Brown MS, Goldstein JL.

Annu Rev Genet. 1990;24:133-70. Review. No abstract available.

PubMed [citation]

PMID:: 2088165

See all PubMed Citations (10)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294986.2

#	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)

#	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

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606232.1

#	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, SCV004830243.1

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

Description

This missense variant (also known as p.Cys249Tyr in the mature protein) replaces cysteine with tyrosine at codon 270 in the LDLR type A repeat 6 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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 heterozygous familial hypercholesterolemia (PMID: 1301956, 23375686, 30270083, 34220717). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 7903864, 15637307; doi:10.1016/j.rccar.2019.10.006 Ruiz 2020). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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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