NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 23, 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:: RCV000775084.10

Allele description [Variation Report for NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr)]

NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr)

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.2000G>A (p.Cys667Tyr)

Other names:

C646Y; FH French Canadian 2; FH French Canadian-2; NP_000518.1:p.C667Y; NM_000527.5(LDLR):c.2000G>A

HGVS:

NC_000019.10:g.11120382G>A
NG_009060.1:g.36002G>A
NM_000527.5:c.2000G>AMANE SELECT
NM_001195798.2:c.2000G>A
NM_001195799.2:c.1877G>A
NM_001195800.2:c.1496G>A
NM_001195803.2:c.1606+149G>A
NP_000518.1:p.Cys667Tyr
NP_000518.1:p.Cys667Tyr
NP_001182727.1:p.Cys667Tyr
NP_001182728.1:p.Cys626Tyr
NP_001182729.1:p.Cys499Tyr
LRG_274t1:c.2000G>A
LRG_274:g.36002G>A
LRG_274p1:p.Cys667Tyr
NC_000019.9:g.11231058G>A
NM_000527.4:c.2000G>A
P01130:p.Cys667Tyr
c.2000G>A

Protein change:

C499Y; CYS646TYR

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000274; UniProtKB: P01130#VAR_005407; OMIM: 606945.0015; dbSNP: rs28942083

NCBI 1000 Genomes Browser:

rs28942083

Molecular consequence:

NM_001195803.2:c.1606+149G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2000G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2000G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1877G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1496G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV000052786	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 14, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 15241806, 10206683, 12406975, 17426749, 11668627, 18263977, 18239150, 19081415, 19318025, 19446849, 23375686, 2318961, 35052492 Citation Link,
SCV000909188	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 12, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000930819	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 10206683, 11810272, 15241806, 18263977, 23375686, 27765764, 2318961, 7548065, 7603991, 7979249, 18325082, 9412789, 11313767, 15701167, 24507775, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000052786

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 14, 2023)

germline

clinical testing

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

Citation Link,

SCV000909188

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 12, 2018)

germline

clinical testing

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

SCV000930819

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 2023)

germline

clinical testing

PubMed (16)
[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

Use of denaturing HPLC to provide efficient detection of mutations causing familial hypercholesterolemia.

Bodamer OA, Bercovich D, Schlabach M, Ballantyne C, Zoch D, Beaudet AL.

Clin Chem. 2002 Nov;48(11):1913-8.

PubMed [citation]

PMID:: 12406975

Genetic susceptibility to heart disease in Canada: lessons from patients with familial hypercholesterolemia.

Hegele RA.

Genome. 2006 Nov;49(11):1343-50. Review.

PubMed [citation]

PMID:: 17426749

See all PubMed Citations (25)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052786.3

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

Description

Variant summary: LDLR c.2000G>A (p.Cys667Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.2000G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_2013, Bodamer_2002, Cenarro_1998, Leitersdorf_1990, Madar_2022, Kublaska_2008). Additionally, other missense variants in the same residue (p.C667F, p.C667R, p.C667S and p.C667W) have all been classified pathogenic/likely pathogenic in ClinVar, supporting the functional importance of this residue of the protein. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating effect on protein processing (Leitersdorf_1990). The following publications have been ascertained in the context of this evaluation (PMID: 23375686, 12406975, 10206683, 18263977, 35052492, 2318961). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/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 Color Diagnostics, LLC DBA Color Health, SCV000909188.1

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

Description

Pathogenic variant based on current evidence: This missense variant (also known as p.Cys646Tyr in the mature protein and as FH French Canadian-2) is located in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that this variant abolishes maturation and transport of the LDLR protein to the cell surface (PMID: 2318961). While this variant is rare in the general population (1/246206 chromosomes in the Genome Aggregation Database (gnomAD)), this variant has been reported in over 30 individuals diagnosed with familial hypercholesterolemia (PMID: 2318961, 10206683, 11810272, 18263977, 25278291) and particularly common in the French Canadian population (PMID: 2318961). Based on available evidence this variant is 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 Invitae, SCV000930819.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 667 of the LDLR protein (p.Cys667Tyr). This variant is present in population databases (rs28942083, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2318961, 10206683, 11810272, 15241806, 18263977, 23375686, 27765764). This variant is also known as p.Cys646Tyr. ClinVar contains an entry for this variant (Variation ID: 3689). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 2318961). 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). This variant disrupts the p.Cys667 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9412789, 11313767, 15701167, 24507775), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been 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

Last Updated: Jun 23, 2024

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