chr19-11113376-G-A

Variant names:

• chr19-11113376-G-A
• rs28942078
• NM_000527.5:c.1285G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS4 PP1_Strong PM2 PP3 PP4 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1285G>A (p.Val429Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows:PM2: PopMax MAF = 0.00003266 (0.003%) in South Asian exomes (gnomAD v2.1.1). PP3: REVEL = 0.809. PS3_Moderate: Level 2 assay – PMID 2569482 (Leitersdorf et al., 1989) - Immunoprecipitation assay on heterozygous CHO cells where the receptor was degraded more rapidly. After 6 h, only 13% of the LDL receptor protein remained. Level 2 assay – PMID 3202825 (Fourie et al., 1988) - 125I-labelled LDL assay on homozygous patient's fibroblasts with overall LDL receptor activity of ~2% of wildtype. PS4, PP4: Variant meets PM2 and is identified in at least 55 unrelated index cases who fulfill criteria for FH- 1 case with DLCN score >=6 from Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain;- 4 cases with DLCN score >=6 from Robarts Research Institute, Canada;- 9 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia;- 2 cases with DLCN score >=6 and 1 case with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France;- 2 cases with possible FH by Simon Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 36 cases fulfilling MEDPED criteria from PMID 8399083 (Kotze et al., 1993), South Africa. PP1_Strong: Variant segregates with FH phenotype in 27 informative meiosis from at least 10 families from different labs (Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain; Robarts Research Institute, Canada; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; Laboratory of Genetics and Molecular Cardiology, Brazil; PMID 26036859 (Brænne et al., 2016), Germany; PMID 21925660 (Versmissen et al., 2011), the Netherlands): 19 affected family members have the variant and 8 unaffected family members do not have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023443/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:34 O:1
• Conservation: PhyloP100: 2.72
• Publications: 61 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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 14 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.
• 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.1285G>A	p.Val429Met	missense	Exon 9 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1285G>A	p.Val429Met	missense	Exon 9 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1162G>A	p.Val388Met	missense	Exon 8 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.1285G>A	p.Val429Met	missense	Exon 9 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1543G>A	p.Val515Met	missense	Exon 9 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1285G>A	p.Val429Met	missense	Exon 9 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251284 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727158

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

American (AMR) AF: 0.0000447 AC: 2 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: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

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

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112004

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
22	-	-	Hypercholesterolemia, familial, 1 (22)
5	-	-	not provided (5)
4	-	-	Familial hypercholesterolemia (5)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	LDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.52
MutPred		0.86		Gain of phosphorylation at T434 (P = 0.1319)
MVP		1.0
MPC		0.77
ClinPred		0.82	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
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: rs28942078; hg19: chr19-11224052; COSMIC: COSV52944609; COSMIC: COSV52944609;