19-11116900-C-T

Variant names:

• chr19-11116900-C-T
• rs730882109
• NM_000527.5:c.1747C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PS4 PP1_Strong PM3 PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.001203 (0.12%) in East Asian (gnomAD v2.1.1). PopMax MAF > 0.02% (PM2 is "not met"), however, after reviewing literature cases, a founder effect - mostly Asian ancestry - seems to be associated (PMID 27206935 - Chiou et al. 2016; several case reports used for PS4). This variant was also found in other populations: PopMax MAF = 0.016% in South Asian (gnomAD v2.1.1). PP3: REVEL = 0.884. PS3: Functional studies reported in PMID 32695144 (Dušková et al., 2020) performed using heterologous cells (CHO), WB and FACS - results - 52% expression and 44% internalization. The variant showed a deleterious effect on the protein localization and function, and was associated with the accumulation of the protein in the ER. Results are below 70%, so PS3 is met. // Functional studies reported in PMID 21511053 (Zhao et al., 2011) performed using retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays - results - approximately 50% cell surface LDLR, 50-60% LDL-LDLR uptake and normal LDL-LDLR binding. Results are below 70%, so PS3 is met. -------- Overall, both functional studies are consistent with damaging effect.PS4, PP4: Variant meets PM2 and is identified in at least 17 unrelated index cases fulfilling criteria for FH (2 index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; at least 15 cases from PMID 20538126, 22353362, 21376320, 25846081, 19318025).PP1_Strong: Variant segregates with FH phenotype in at least 9 informative meioses (minimum 6) from 3 families from different PMIDs (23155708, 2923363, 22353362): 9 affected family members have the variant.PM3: Variant meets PM2 and is identified in 1 index case (PMID 7903864) with homozygous FH phenotype and a deletion of LDLR exons 4-11, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 23155708) with homozygous FH phenotype and the LDLR c.2054C>T, p.(Pro685Leu) variant, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 29233637) with homozygous FH phenotype and the LDLR c.724C>T, p.(Gln242*) variant, confirmed in trans, classified as Pathogenic by these guidelines. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023567/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:29 B:1
• Conservation: PhyloP100: 6.03
• Publications: 59 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: Pathogenic. The variant received 18 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.
• 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.

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.1747C>T	p.His583Tyr	missense	Exon 12 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1747C>T	p.His583Tyr	missense	Exon 12 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1624C>T	p.His542Tyr	missense	Exon 11 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.1747C>T	p.His583Tyr	missense	Exon 12 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2005C>T	p.His669Tyr	missense	Exon 12 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1747C>T	p.His583Tyr	missense	Exon 12 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251488 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461782 Hom.: 1 Cov.: 35 AF XY: 0.0000316 AC XY: 23 AN XY: 727198

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: 26136

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111940

Other (OTH) AF: 0.000116 AC: 7 AN: 60388

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74332

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

American (AMR) AF: 0.00 AC: 0 AN: 15256

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

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000906 AC: 11

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
15	-	1	Hypercholesterolemia, familial, 1 (16)
6	-	-	Familial hypercholesterolemia (6)
5	-	-	not provided (5)
2	-	-	Homozygous familial hypercholesterolemia (2)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.86		Gain of sheet (P = 0.0344)
MVP		1.0
MPC		0.87
ClinPred		0.45	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs730882109; hg19: chr19-11227576; COSMIC: COSV52942043; COSMIC: COSV52942043;