NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Feb 9, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000238286.8

Allele description [Variation Report for NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr)]

NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr)

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.974G>A (p.Cys325Tyr)

Other names:

NM_000527.5(LDLR):c.974G>A; p.Cys325Tyr

HGVS:

NC_000019.10:g.11110685G>A
NG_009060.1:g.26305G>A
NM_000527.5:c.974G>AMANE SELECT
NM_001195798.2:c.974G>A
NM_001195799.2:c.851G>A
NM_001195800.2:c.470G>A
NM_001195803.2:c.593G>A
NP_000518.1:p.Cys325Tyr
NP_000518.1:p.Cys325Tyr
NP_001182727.1:p.Cys325Tyr
NP_001182728.1:p.Cys284Tyr
NP_001182729.1:p.Cys157Tyr
NP_001182732.1:p.Cys198Tyr
LRG_274t1:c.974G>A
LRG_274:g.26305G>A
LRG_274p1:p.Cys325Tyr
NC_000019.9:g.11221361G>A
NM_000527.4:c.974G>A
c.974G>A
p.(Cys325Tyr)

Protein change:

C157Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001893; dbSNP: rs879254746

NCBI 1000 Genomes Browser:

rs879254746

Molecular consequence:

NM_000527.5:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.851G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.470G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.593G>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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protein unc-119 homolog B [Mus musculus]
protein unc-119 homolog B [Mus musculus]
gi|30425054|ref|NP_780561.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295121	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000607539	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 21865347
SCV001432620	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001653614	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19318025, 21865347, 30526649, 31491741, 32977124, 25741868
SCV002506391	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Feb 9, 2022)	germline	curation	Citation Link,
SCV002806168	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	3	not provided	literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation
Caucasian	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

Trinder M, Li X, DeCastro ML, Cermakova L, Sadananda S, Jackson LM, Azizi H, Mancini GBJ, Francis GA, Frohlich J, Brunham LR.

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.

PubMed [citation]

PMID:: 31345425

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

See all PubMed Citations (7)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295121.2

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

#	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

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607539.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

"Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays"

PubMed [ID: 21865347]

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432620.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	not provided	1	not provided	not provided	research	PubMed (2)

#	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

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653614.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	3	not provided	not provided	clinical testing	PubMed (6)

Description

Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.

#	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		3	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506391.1

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

Description

The NM_000527.5 (LDLR): c. 974G>A (p.Cys325Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM1, PS4_Moderate, PP3, PP4, PS3_Supporting,) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP3 Met: REVEL = 0.977, which is above the threshold of 0.75. PM1 Met: The variant meets PM2, and alters Cys325, which is located in EGF-like 1 domain and is one of 60 highly conserved cysteine residues. PS3_Supporting Met: FACS assay using heterozygous patients’ lymphocytes (level 3 functional assay) showed 50-60% LDLR activity compared to wild type, from one research lab (CEINGE-Biotecnologie Avanzate, Napoli, Italy, PMID21865347). PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Moderate Met: Variant meets PM2 and is identified in 8 unrelated index cases. Five of the index cases fulfil DLCN criteria for FH from 5 different laboratories (1 case from Mayo Clinic Atherosclerosis and Lipid genomics Laboratory, LabID500068; 1 case from University of Genova-University of Modena and Reggio Emilia, Italy, PMID32977124; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Spain, PMID19318025; 1 case from Centre for Heart Lung Innovation, University of British Columbia, Canada, PMID31345425; and 1case from Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, China, PMID30526649). One index case fulfil FH diagnosis criteria established by the Societa Italiana per lo Studio della Arteriosclerosi, CEINGE-Biotecnologie Avanzate, Napoli, Italy, PMID21865347. Two index cases fulfil Japanese FH guidelines, from Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan, PMID31491741. There are three other variants in the same codon: LDLR: NM_000527: c.973T>C (p.Cys325Arg), LDLR: NM_000527: c.974G>C (p.Cys325Ser), LDLR: NM_000527: c.974G>T (p.Cys325Phe), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002806168.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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