rs769370816

Variant names:

• chr19-11116125-G-A
• rs769370816
• NM_000527.5:c.1618G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11116125-G-A
• chr19-11116125-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS4 PP1_Strong PM3 PS3_Supporting PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Strong, PM2, PM3, 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: PS4 - variant meets PM2 and was identified in:- at least 1 index case with DLCN at least 8 (TC =700mg/dl) from Ambry Genetics, USA;- 14 unrelated index cases, all with DLCN >=6 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 5 unrelated index cases (3 with Simon Broome definite FH, 2 with Simon Broome possible FH) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 4 unrelated index cases, all with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia;- 2 unrelated index cases, all with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada;- at least 1 index case with DLCN>=6 from PMID 19318025 (Alonso et al., 2009), Spain;- at least 1 index case with SB criteria for FH from PMID 21376320 Chiou et al., 2011), Taiwan,--- 30 cases, so PS4 is metPP1_strong - variant segregates with the FH phenotype in 39 informative meiosis from at least 14 families:- 20 informative meiosis from 7 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: 16 relatives with the variant have LDL-C >75th percentile, and 4 relatives without the variant have LDL-C <50th percentile;- 1 informative meiosis 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 relative positive for variant had LDL-C >75th percentile;- 8 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): F1 with 2 relatives positive for variant and having LDL-C >75th percentile, and 2 relatives negative for variant and having LDL-C <50th percentile, F2: 1 relative who was positive for the variant and had LDL-C >75th percentile, F3: 2 relatives who were positive for variant with LDL-C >75th percentile, and 1 relative who was negative for the variant with LDL-C <50th percentile;- 2 informative meiosis from 2 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative positive for variant with LDL-C >75th percentile in each family;- 8 informative meiosis (unknown how many families) from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 5 relatives positive for variant with LDL-C >75th percentile, and 3 relatives were negative for variant with LDL-C <50th percentile.--- 39 segregations, so PP1_Strong is metPM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian exomes (gnomAD v2.1.1). It is below than 0.02%, so PM2 is met.PM3 - variant meets PM2 and was identified in:- 1 index case homozygous for the variant with TC = 700mg/dl at 7 years old from Ambry Genetics. ---> individual is homozygous for variant and has an homozygous phenotype, so PM3 is met.- 2 unrelated index cases, both homozygous for the variant, with LDL-C 352mg/dL under statin treatment (352/0.7 = 503mg/dl) and LDL-C=409mg/dl under statin treatment (409/0.7 = 584mg/dl), respectively, both from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) ---> individuals are homozygous for variant and have an homozygous phenotype, so PM3 is met.PP3 - REVEL = 0.888. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 30 unrelated index cases who fulfill clinical FH criteria (see PS4 for details), so PP4 is met.PS3_supporting - Level 3 FS: Sun et al., 1997 (PMID 9409298) - Htz patients' fibroblasts, immunoblot and 125I-LDL assays - results: 40-50% LDLR activity, cell surface LDLR 40-50% LDLR.--- Activity is below 85%, so PS3_Supporting is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA035437/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:26
• Conservation: PhyloP100: 7.97
• Publications: 18 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 15 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.1618G>A	p.Ala540Thr	missense	Exon 11 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1618G>A	p.Ala540Thr	missense	Exon 11 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1495G>A	p.Ala499Thr	missense	Exon 10 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.1618G>A	p.Ala540Thr	missense	Exon 11 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1876G>A	p.Ala626Thr	missense	Exon 11 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1618G>A	p.Ala540Thr	missense	Exon 11 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251472 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461164 Hom.: 1 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726916

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111422

Other (OTH) AF: 0.0000331 AC: 2 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
19	-	-	Hypercholesterolemia, familial, 1 (19)
3	-	-	not provided (3)
2	-	-	Familial hypercholesterolemia (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.89		Gain of ubiquitination at K543 (P = 0.0849)
MVP		1.0
MPC		0.79
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.75
gMVP		0.98
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: rs769370816; hg19: chr19-11226801;