rs515726148

Variant names:

• chr19-44908791-GCTC-G
• rs515726148
• NM_000041.4:c.500_502delTCC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM4_Supporting PP5_Very_Strong

The NM_000041.4(APOE):​c.500_502delTCC​(p.Leu167del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,553,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002642401: Functional studies indicate L167del leads to increased uptake of VLDL and a subsequent decrease in LDLR membrane expression (Cenarro A et al. J. Clin. Endocrinol. Metab., 2016 05" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: APOE NM_000041.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.04
• Publications: 40 publications found

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

APOE Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002642401: Functional studies indicate L167del leads to increased uptake of VLDL and a subsequent decrease in LDLR membrane expression (Cenarro A et al. J. Clin. Endocrinol. Metab., 2016 05;101:2113-21).; SCV005684986: Functional studies indicate that this variant leads to increased uptake of VLDL and a subsequent decrease in LDLR membrane expression (PS3_STRONG; PMID 27014949).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000041.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000041.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-44908791-GCTC-G is Pathogenic according to our data. Variant chr19-44908791-GCTC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 126456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000041.4. 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
	APOE	NM_000041.4	MANE Select	c.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 4 of 4	NP_000032.1	A0A0S2Z3D5
	APOE	NM_001302688.2		c.578_580delTCC	p.Leu193del	disruptive_inframe_deletion	Exon 4 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 4 of 4	NP_001289618.1	P02649

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000252486.3	P02649
	APOE	ENST00000425718.1	TSL:1	c.500_502delTCC	p.Leu167del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000410423.1	E7ERP7
	APOE	ENST00000864831.1		c.554_556delTCC	p.Leu185del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000534890.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 3 AN: 149924 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000784

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000170

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000428 AC: 60 AN: 1401718 Hom.: 0 AF XY: 0.0000375 AC XY: 26 AN XY: 692832

African (AFR) AF: 0.00 AC: 0 AN: 32168

American (AMR) AF: 0.0000814 AC: 3 AN: 36856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 36608

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4852

European-Non Finnish (NFE) AF: 0.0000507 AC: 55 AN: 1085186

Other (OTH) AF: 0.0000172 AC: 1 AN: 58160

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	APOE-related disorder (3)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial hypercholesterolemia (1)
1	-	-	Sea-blue histiocyte syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=62/38	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: rs515726148; hg19: chr19-45412048;