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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 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:: RCV001328351.5

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]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001519441	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 12, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301956, 7903864, 19026292, 23375686, 30270083, 15637307, 34220717 Citation Link,
SCV003443154	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 16, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 11754108, 16250003, 7548065, 7603991, 7979249, 18325082, 7903864, 1301956, 15637307, 23375686, 29233637, 30270083, 28492532
SCV004358495	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 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

SCV001519441

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 12, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV003443154

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 16, 2022)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV004358495

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia.

Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE, Araujo L, Vohra Y, Defesche JC, Wilson JM, Rader DJ.

Am J Cardiol. 2008 Dec 1;102(11):1438-43. doi: 10.1016/j.amjcard.2008.07.035. Epub 2008 Sep 11.

PubMed [citation]

PMID:: 19026292

Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients.

Kuhrová V, Francová H, Zapletalová P, Freiberger T, Fajkusová L, Hrabincová E, Slováĉková R, Kozák L, Slováková R.

Hum Mutat. 2002 Jan;19(1):80.

PubMed [citation]

PMID:: 11754108

See all PubMed Citations (19)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001519441.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: LDLR c.809G>A (p.Cys270Tyr) results in a non-conservative amino acid change located in the sixth class A repeat (IPR002172) of the encoded protein sequence. The class A repeats form the binding sites for LDL and contain six cysteine residues involved in disulfide bond formation that is required for structural integrity (InterPro). Numerous missense changes affecting cysteine residues within LDLR class A repeats are found among patients with hypercholesterolemia (HGMD), in addition, other variants affecting the same residue (i.e. Cys270), have been reported in affected individuals. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes (gnomAD). The variant, c.809G>A, (aka. c.Cys249Tyr or FH-Miami-2) has been reported in the literature in heterozygous- and compound heterozygous state in individuals affected with Familial Hypercholesterolemia (e.g. Hobbs_1992, Sun_1994, Millar_2005, Kolansky_2008, Bertolini_2013, Hsiung_2018, Yang_2021). These data indicate that the variant is very likely to be associated with disease. In one family the variant was also found in an affected family member (Yang_2021), however, in another study the variant was also reported in at least one seemingly unaffected family member (Sun_1994), which might indicate an incomplete penetrance. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated impaired LDLR activity and ligand binding in patient derived fibroblast (Hobbs_1992) and in an in-vitro expression system (Sun_1994). Another clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003443154.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 270 of the LDLR protein (p.Cys270Tyr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys270 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11754108, 16250003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Experimental studies have shown that this missense change affects LDLR function (PMID: 7903864). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251464). This variant is also known as C249Y or FH Miami-2. This missense change has been observed in individuals with autosomal dominant and autosomal recessive familial hypercholesterolemia (PMID: 1301956, 15637307, 23375686, 29233637, 30270083). This variant is not present in population databases (gnomAD no frequency).

#	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 Color Diagnostics, LLC DBA Color Health, SCV004358495.1

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

Last Updated: Sep 29, 2024

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