19-44908774-C-T

Position:

• chr19-44908774-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000041.4(APOE):​c.478C>T​(p.Arg160Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.438

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 31) in uniprot entity APOE_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000041.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 19-44908774-C-T is Pathogenic according to our data. Variant chr19-44908774-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 487346.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4	c.478C>T	p.Arg160Cys	missense_variant	4/4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.478C>T	p.Arg160Cys	missense_variant	4/4	1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000425718.1	c.478C>T	p.Arg160Cys	missense_variant	3/3	1		ENSP00000410423.1
APOE	ENST00000434152.5	c.556C>T	p.Arg186Cys	missense_variant	4/4	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.478C>T	p.Arg160Cys	missense_variant	4/4	2		ENSP00000413135.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408050 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 696150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000270 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial type 3 hyperlipoproteinemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Aug 22, 2022

The c.478C>T variant has previously been reported to co-segregate with autosomal dominant familial dysbetalipoproteinemia is a family in whom six affected and four unaffected family-members were tested [PMID: 2539388]. The variant was located on the apoE4 allele [PMID: 2539388]. The c.478C>T variant is absent from population databases (gnomAD v2.1.1 andv3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases.The c.478C>T variant is located in exon 4 of this 4-exon gene and is predicted to replace an evolutionarily conserved arginine residue with cysteine at position 160 inthe alpha-helical segment of the encoded protein [PMID: 22645694]. Two different variants [p.(Arg160Leu) and p.(Arg160Ser)] affecting the same Arg160 codon have been reported in individuals with hyperlipidemia phenotype [PMID: 7772063, 15256764,24953047]. In silico predictions are in favor of damaging effect for thep.(Arg160Cys) variant [REVEL = 0.827]. In vitro functional studies revealed a significantly reduced receptor-binding and heparin-binding activity for p.(Arg160Cys)[PMID: 2539388, 11500500, 34058468]. This individual has apoE2/apoE3 genotype and the p.(Arg160Cys) variant is located on the apoE2 allele. Based on available evidence this c.478C>T p.(Arg160Cys) variant identified in APOE is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;D;.;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.32
MutPred		0.92		Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);.;Loss of disorder (P = 0.0183);
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906567; hg19: chr19-45412031;