NM_000527.5(LDLR):c.1103G>A (p.Cys368Tyr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 1, 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:: RCV000781493.10

Allele description [Variation Report for NM_000527.5(LDLR):c.1103G>A (p.Cys368Tyr)]

NM_000527.5(LDLR):c.1103G>A (p.Cys368Tyr)

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.1103G>A (p.Cys368Tyr)

HGVS:

NC_000019.10:g.11111556G>A
NG_009060.1:g.27176G>A
NM_000527.5:c.1103G>AMANE SELECT
NM_001195798.2:c.1103G>A
NM_001195799.2:c.980G>A
NM_001195800.2:c.599G>A
NM_001195803.2:c.722G>A
NP_000518.1:p.Cys368Tyr
NP_000518.1:p.Cys368Tyr
NP_001182727.1:p.Cys368Tyr
NP_001182728.1:p.Cys327Tyr
NP_001182729.1:p.Cys200Tyr
NP_001182732.1:p.Cys241Tyr
LRG_274t1:c.1103G>A
LRG_274:g.27176G>A
LRG_274p1:p.Cys368Tyr
NC_000019.9:g.11222232G>A
NM_000527.4:c.1103G>A
P01130:p.Cys368Tyr
c.1103G>A

Protein change:

C200Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001357; UniProtKB: P01130#VAR_072844

Molecular consequence:

NM_000527.5:c.1103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.980G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.599G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.722G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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RPS14B ribosomal 40S subunit protein S14B [Saccharomyces cerevisiae S288C]
RPS14B ribosomal 40S subunit protein S14B [Saccharomyces cerevisiae S288C]
Gene ID:853248

Gene
Gene Links for GEO Profiles (Select 66725651) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000824206	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 1, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 1310940, 21722902, 23064986, 25461735, 26081744, 7548065, 7603991, 7979249, 18325082, 9452094, 27765764, 28492532
SCV000919571	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 17, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15241806, 16314194, 1301940, 21722902, 23064986, 25461735, 26802169, 30293936, 32015373 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824206

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 1, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000919571

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 17, 2022)

germline

clinical testing

PubMed (9)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A comparative study on the catalytic properties of guanyl-specific ribonucleases.

Yakovlev GI, Moiseyev GP, Bezborodova SI, Both V, Sevcik J.

Eur J Biochem. 1992 Feb 15;204(1):187-90.

PubMed [citation]

PMID:: 1310940

Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model.

Bissig-Choisat B, Wang L, Legras X, Saha PK, Chen L, Bell P, Pankowicz FP, Hill MC, Barzi M, Leyton CK, Leung HE, Kruse RL, Himes RW, Goss JA, Wilson JM, Chan L, Lagor WR, Bissig KD.

Nat Commun. 2015 Jun 17;6:7339. doi: 10.1038/ncomms8339.

PubMed [citation]

PMID:: 26081744
PMCID:: PMC4557302

See all PubMed Citations (19)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824206.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 368 of the LDLR protein (p.Cys368Tyr). This variant is present in population databases (rs768430352, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1310940, 21722902, 23064986, 25461735, 26081744). This variant is also known as p.Cys347Tyr. ClinVar contains an entry for this variant (Variation ID: 251665). 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.Cys368 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452094, 27765764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV000919571.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: LDLR c.1103G>A (p.Cys368Tyr) 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 1.2e-05 in 251548 control chromosomes. c.1103G>A has been reported in the literature in many individuals affected with Familial Hypercholesterolemia (example Loux_1992, Mozas_2004, Robles-Osorio_2006, Ahmad_2012, Jannes_2015, Wintjens_2016, Martin-Campos_2018). 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. The Cys368Tyr variant was found to have reduced LDL-LDLR binding activity and LDL uptake, 40% and 60% than that of wild type, repectively (Galicia-Garcia_2020). Six clinical diagnostic laboratories and four research groups have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4 pathogenic, 3 likely pathogenic, and 3 VUS). 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 Cohesion Phenomics, SCV003836761.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003836761	Cohesion Phenomics	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Benign (Feb 9, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003836761

Cohesion Phenomics

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Benign
(Feb 9, 2023)

germline

clinical testing

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

Last Updated: Sep 29, 2024

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Relating variation to medicine