19-11105436-C-T

Variant names:

• chr19-11105436-C-T
• rs121908026
• NM_000527.5:c.530C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 20P and 4B. PS3 PS4 PP1_Strong PM1 PM3 BS4 PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR): c.530C>T (p.Ser177Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PM1, PM2, PM3, PP1_Strong, PP3, PP4 and BS4) 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:PS3 - PMID:31578082 - Level 1 assay - Heterologous cells (CHO), FACS assays and CLSM: 65% cell surface LDLR, 10% binding and <2% uptake. PMID:2760205 - Level 2 assay - Homozygous patient fibroblast, 125I-LDL assays: <2% LDLR activity. PMID:25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assays: LDLR activity decreased compared to WT - considered as disruptive.PS4 - Variant meets PM2. Variant identified in 30 unrelated index cases (5 cases (2 with DLCN≥6; 3 with Simon-Broome possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Simon-Broome possible from GeneDx Inc.; 11 cases with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 13 cases with Simon-Broome possible/definite from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PM1 - Variant meets PM2 and is missense in exon 4.PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes+genomes (gnomAD v2.1.1).PM3 - Patient 3 from PMID:18263977 has LDL = 19.7 mmol/l and also LDLR p.Arg350* in trans - Pathogenic by these guidelines. Two true homozygotes (FHF23 and FHF57) published in PMID:27816806 had LDL = 16.2 mmol/l and 22.6 mmol/l, respectively.PP1_Strong - Variant segregates with FH phenotype in 52 informative meiosis in 26 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 43 relatives tested positive had LDL-C >75th percentile + 9 relatives tested negative had LDL-C <50th percentile.PP3 - REVEL = 0.886.PP4 - Variant meets PM2. Variant identified in 30 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details).BS4 - Variant does not segregate with phenotype in 14 informative meiosis from at least 6 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 13 relatives tested negative but had LDL-C >75th percentile + 1 relative tested positive but LDL-C <50th percentile.Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023715/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:27 O:1
• Conservation: PhyloP100: 4.87
• Publications: 32 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.
• BS4: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.530C>T	p.Ser177Leu	missense	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.530C>T	p.Ser177Leu	missense	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.407C>T	p.Ser136Leu	missense	Exon 3 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.530C>T	p.Ser177Leu	missense	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.788C>T	p.Ser263Leu	missense	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.530C>T	p.Ser177Leu	missense	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251308 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461728 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152202 Hom.: 1 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.000196 AC: 3 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00793067), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000194 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
17	-	-	Hypercholesterolemia, familial, 1 (17)
6	-	-	Familial hypercholesterolemia (6)
3	-	-	not provided (4)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.72		Loss of disorder (P = 0.0252)
MVP		1.0
MPC		0.76
ClinPred		0.96	D
GERP RS		5.6
PromoterAI		0.0012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
gMVP		0.99
Mutation Taster		=1/99	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: rs121908026; hg19: chr19-11216112;