chr19-11110685-G-A

Variant names:

• chr19-11110685-G-A
• rs879254746
• NM_000527.5:c.974G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS4_Moderate PM1 PS3_Supporting PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585234/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.68
• Publications: 7 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.974G>A	p.Cys325Tyr	missense	Exon 7 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.974G>A	p.Cys325Tyr	missense	Exon 7 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.851G>A	p.Cys284Tyr	missense	Exon 6 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.974G>A	p.Cys325Tyr	missense	Exon 7 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1232G>A	p.Cys411Tyr	missense	Exon 7 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.974G>A	p.Cys325Tyr	missense	Exon 7 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461568 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111964

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000430 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Hypercholesterolemia, familial, 1 (6)
2	-	-	Familial hypercholesterolemia (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dyslipidemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		9.7
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Loss of disorder (P = 0.1727)
MVP		1.0
MPC		0.61
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879254746; hg19: chr19-11221361;