NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Apr 25, 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:: RCV000211658.12

Allele description [Variation Report for NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr)]

NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr)

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.326G>A (p.Cys109Tyr)

Other names:

NP_000518.1:p.C109Y

HGVS:

NC_000019.10:g.11105232G>A
NG_009060.1:g.20852G>A
NM_000527.5:c.326G>AMANE SELECT
NM_001195798.2:c.326G>A
NM_001195799.2:c.203G>A
NM_001195800.2:c.314-2160G>A
NM_001195803.2:c.314-1333G>A
NP_000518.1:p.Cys109Tyr
NP_000518.1:p.Cys109Tyr
NP_001182727.1:p.Cys109Tyr
NP_001182728.1:p.Cys68Tyr
LRG_274t1:c.326G>A
LRG_274:g.20852G>A
LRG_274p1:p.Cys109Tyr
NC_000019.9:g.11215908G>A
NM_000527.4:c.326G>A
c.326G>A

Protein change:

C109Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000051; dbSNP: rs121908042

NCBI 1000 Genomes Browser:

rs121908042

Molecular consequence:

NM_001195800.2:c.314-2160G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1333G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.203G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268557	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jul 22, 2008)	germline	clinical testing
SCV000294631	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 11313767, 20145306, 21310417, 16465405 Citation Link,
SCV000484762	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606087	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004175578	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005417140	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005426440	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 25, 2024)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 2088165, 6091915, 9026534, 11313767, 15952897, 17094996, 17539906, 20145306, 22883975, 23833242, 24075752, 24956927, 27050191, 32276786, 33418990, 33740630, 34037665, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	10	not provided	not provided	4	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	143475	not provided	clinical testing, research

Citations

PubMed

An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia.

Dušková L, Kopečková L, Jansová E, Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2011 May;216(1):139-45. doi: 10.1016/j.atherosclerosis.2011.01.023. Epub 2011 Jan 21.

PubMed [citation]

PMID:: 21310417

Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent.

Cefalù AB, Barraco G, Noto D, Valenti V, Barbagallo CM, Elisir GD, Cuniberti LA, Werba JP, Libra M, Costa S, Gianguzza F, Notarbartolo A, Travali S, Averna MR.

Int J Mol Med. 2006 Mar;17(3):539-46.

PubMed [citation]

PMID:: 16465405

See all PubMed Citations (21)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268557.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

#	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		5	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294631.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (4)
2	not provided	1	not provided	not provided	literature only	PubMed (4)
3	not provided	1	not provided	not provided	literature only	PubMed (4)
4	not provided	1	not provided	not provided	literature only	PubMed (4)

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

From Robarts Research Institute, Western University, SCV000484762.1

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

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606087.1

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

#	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 Genetics and Molecular Pathology, SA Pathology, SCV004175578.1

#	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

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005417140.1

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

Description

PM2_Supporting+PS4_Moderate+PP4+PM1+PP3_Strong

#	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

From All of Us Research Program, National Institutes of Health, SCV005426440.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (18)

Description

This missense variant (also known as p.Cys88Tyr in the mature protein) replaces cysteine with tyrosine at codon 109 in the LDLR type A repeat 3 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 LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9026534, 11313767, 17094996, 17539906, 20145306, 22883975, 23833242, 24075752, 33418990, 33740630, 34037665). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia and extensive atherosclerotic cardiovascular disease, a phenotype expected of having two deleterious LDLR variants (PMID: 22883975, 32276786). Additionally, this variant has been reported in an individual affected with coronary artery disease (PMID: 27050191) and in an individual affected with moderately high total cholesterol despite cholesterol-lowering therapy (PMID: 24956927). This variant has been identified in 1/250250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the 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	143475	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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