NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 2, 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:: RCV001535532.16

Allele description [Variation Report for NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr)]

NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr)

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.551G>A (p.Cys184Tyr)

Other names:

C163Y; FH Glasco; FH Rome-2; NP_000518.1:p.C184Y; NM_000527.5(LDLR):c.551G>A

HGVS:

NC_000019.10:g.11105457G>A
NG_009060.1:g.21077G>A
NM_000527.5:c.551G>AMANE SELECT
NM_001195798.2:c.551G>A
NM_001195799.2:c.428G>A
NM_001195800.2:c.314-1935G>A
NM_001195803.2:c.314-1108G>A
NP_000518.1:p.Cys184Tyr
NP_000518.1:p.Cys184Tyr
NP_001182727.1:p.Cys184Tyr
NP_001182728.1:p.Cys143Tyr
LRG_274t1:c.551G>A
LRG_274:g.21077G>A
LRG_274p1:p.Cys184Tyr
NC_000019.9:g.11216133G>A
NM_000527.4:c.551G>A
P01130:p.Cys184Tyr
c.551G>A
p.(Cys184Tyr)

Protein change:

C143Y; CYS163TYR

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000078; UniProtKB: P01130#VAR_013951; OMIM: 606945.0058

Molecular consequence:

NM_001195800.2:c.314-1935G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1108G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.551G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.551G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.428G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Mus musculus SECIS binding protein 2, mRNA (cDNA clone IMAGE:1447063), partial c...
Mus musculus SECIS binding protein 2, mRNA (cDNA clone IMAGE:1447063), partial cds
gi|24433541|gb|BC038877.1|

Nucleotide
SLC35E3 [Gracilinanus agilis]
SLC35E3 [Gracilinanus agilis]
Gene ID:123249282

Gene
Pdw03_5920 [Penicillium digitatum]
Pdw03_5920 [Penicillium digitatum]
Gene ID:26229333

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001749502	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV002046959	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Oct 17, 2020)	unknown	clinical testing	PubMed (25) [See all records that cite these PMIDs] 10559517, 11668627, 11810272, 19837725, 20828696, 9678702, 28873201, 27680772, 25461735, 27765764, 28159968, 10357843, 27824480, 18700895, 22883975, 17539906, 17765246, 23669246, 20236128, 31345425, 16159606, 30586733, 32331935, 32143996, 26467025
SCV002049430	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Nov 19, 2021)	germline	clinical testing	Citation Link,
SCV004169114	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 2, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia.

Graham CA, McClean E, Ward AJ, Beattie ED, Martin S, O'Kane M, Young IS, Nicholls DP.

Atherosclerosis. 1999 Dec;147(2):309-16.

PubMed [citation]

PMID:: 10559517

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent.

Wang J, Huff E, Janecka L, Hegele RA.

Hum Mutat. 2001 Oct;18(4):359.

PubMed [citation]

PMID:: 11668627

See all PubMed Citations (25)

Details of each submission

From GenomeConnect - Invitae Patient Insights Network, SCV001749502.1

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

Description

Variant interpreted as Pathogenic and reported on 11-12-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002046959.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (25)

Description

The variant has been reported in multiple families affected with familial hypercholesterolemia in the published literature (PMID: 24627126 (2014), 25461735 (2015), 27680772 (2016), 27765764 (2016), 31345425 (2019), 32331935 (2020)) as well as in individuals with early-onset myocardial infarction (PMID: 30586733 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. A different variant affecting the same amino acid position has been described as pathogenic. Based on the available information, the variant is predicted to be likely pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049430.1

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

Description

The LDLR c.551G>A; p.Cys184Tyr variant (rs121908039) is reported in the literature in 15 individuals affected with high LDL-C (Sturm 2021). Moreover, this variant has been identified as a recurrent co-segregating allele within three familial hypercholesterolemia families with ten informative meiosis cases (Lee 1998). This variant is also reported in ClinVar (Variation ID: 3739). This variant is found in the general population with an overall allele frequency of 0.0096% (3/31402 alleles) in the Genome Aggregation Database. The cysteine at codon 184 is highly conserved, is involved in disulfide bond formation of LDLR, and computational analyses predict that this variant is deleterious (REVEL: 0.854). Based on available information, this variant is considered to be 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 GeneDx, SCV004169114.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies show that LDL-deficient CHO-ldlA7 cells transfected with the p.(C184Y)-LDL demonstrates impaired binding activity (PMID: 34167030); Also reported as FH Rome-2 and p.(C163Y) due to alternate nomenclature; This variant is associated with the following publications: (PMID: 31447099, 30586733, 9678702, 10559517, 11668627, 11810272, 20236128, 20828696, 25461735, 28873201, 33303402, 32719484, 32331935, 33740630, 33418990, 34037665, 27765764, 34363016, 22883975, 1301956, 32041611, 27680772, 31345425, 34297352, 24627126, 30583242, 34906454, 34167030)

#	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

Last Updated: Nov 3, 2024

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