NM_000527.5(LDLR):c.664T>C (p.Cys222Arg) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 4, 2024
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:: RCV000799446.8

Allele description [Variation Report for NM_000527.5(LDLR):c.664T>C (p.Cys222Arg)]

NM_000527.5(LDLR):c.664T>C (p.Cys222Arg)

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.664T>C (p.Cys222Arg)

Other names:

NP_000518.1:p.C222R; NM_000527.5(LDLR):c.664T>C

HGVS:

NC_000019.10:g.11105570T>C
NG_009060.1:g.21190T>C
NM_000527.5:c.664T>CMANE SELECT
NM_001195798.2:c.664T>C
NM_001195799.2:c.541T>C
NM_001195800.2:c.314-1822T>C
NM_001195803.2:c.314-995T>C
NP_000518.1:p.Cys222Arg
NP_000518.1:p.Cys222Arg
NP_001182727.1:p.Cys222Arg
NP_001182728.1:p.Cys181Arg
LRG_274t1:c.664T>C
LRG_274:g.21190T>C
LRG_274p1:p.Cys222Arg
NC_000019.9:g.11216246T>C
NM_000527.4:c.664T>C
c.664T>C

Protein change:

C181R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000707; dbSNP: rs577934998

NCBI 1000 Genomes Browser:

rs577934998

Molecular consequence:

NM_001195800.2:c.314-1822T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-995T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.664T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.664T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.541T>C - 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
SCV000939108	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15823276, 22883975, 25043216, 7548065, 7603991, 7979249, 18325082, 7573037, 24671153, 28492532
SCV002572225	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22883975, 30293936, 33740630 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000939108

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 4, 2024)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002572225

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 22, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

The molecular basis of familial hypercholesterolaemia in Turkish patients.

Sözen MM, Whittall R, Oner C, Tokatli A, Kalkanoğlu HS, Dursun A, Coşkun T, Oner R, Humphries SE.

Atherosclerosis. 2005 May;180(1):63-71.

PubMed [citation]

PMID:: 15823276

Early development of xanthoma and coronary disease in a young female with homozygous familial hypercholesterolemia.

Zhao X, Bu L, Qin S, Kong D, Fan B, Ge J.

Int J Cardiol. 2014 Sep;176(1):e15-9. doi: 10.1016/j.ijcard.2014.06.083. Epub 2014 Jul 6. No abstract available.

PubMed [citation]

PMID:: 25043216

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000939108.6

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

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 222 of the LDLR protein (p.Cys222Arg). This variant is present in population databases (rs577934998, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15823276, 22883975, 25043216; Invitae). This variant is also known as C201R and c.541T>C. ClinVar contains an entry for this variant (Variation ID: 226332). 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%. 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.Cys222 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 7573037, 24671153), 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572225.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: LDLR c.664T>C (p.Cys222Arg) results in a non-conservative amino acid change in 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 8e-06 in 249776 control chromosomes (gnomAD). c.664T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (examples: Hooper_2012, Martn-Campos_2018, and Leren_2021). These data indicate that the variant is very likely to be associated with disease. Other variants located at the same codon have been reported in association with Hypercholesterolaemia (C222G, C222F, C222W, C222Y; HGMD). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=7) and VUS (n=1). 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

Last Updated: Sep 29, 2024

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