rs201736972

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000384.3(APOB):c.10708C>T(p.His3570Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:3

Conservation

PhyloP100: -0.109

Variant links:

Genes affected

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

APOB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054626286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.10708C>T	p.His3570Tyr	missense_variant	26/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.10708C>T	p.His3570Tyr	missense_variant	26/29	1	NM_000384.3	ENSP00000233242	P1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250924

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135574

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000145

AC:

212

AN:

1461758

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

727174

show subpopulations

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:

0.000112

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000191

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	Reported in patients in association with hypercholesterolemia, hyperlipidemia, coronary heart disease and/or myocardial infarction in published literature (Soufi et al., 2004; Basistova et al., 2007; Liyanage et al., 2008; Kusters et al., 2013; Klancar et al., 2015; Galaska et al., 2016; Mullertz et al., 2018; Juhasz et al., 2020); however, while the variant segregated with disease in some families, it has also been identified in unaffected relatives and is absent in other affected relatives; Also described as H3543Y due to alternate nomenclature; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#431988; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 18325181, 15135245, 26666465, 29598884, 26361156, 23833242, 17046772, 33489595) -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 22, 2021	The p.His3570Tyr variant (also reported as p.His3543Tyr) in APOB has been reported in 7 individuals with hypercholesterolemia, one individual with suspected hypercholesterolemia, one individual with sudden cardiac death and segregated with disease in 3 affected relatives from 2 families, but was not detected in one affected family member (Soufi 2004, Basistova 2007, Liyanage 2008, Galaska 2016, Mullertz 2018). This variant has also been identified in 0.027% (35/128752) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 431988). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia in the general population. Histidine (His) at position 3570 is not conserved in mammals or evolutionarily distant species, and 3 mammals (squirrel, ferret, and Chinese hamster) and 18 other species carry a Tyrosine (Tyr), raising the possibility that this change may be tolerated. Additional computational prediction tools analysis suggest that the p.His3570Tyr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.His3570Tyr variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: PS4_Moderate, BP4_Strong, BS4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 04, 2023	BS4, BP4_strong, PS4_moderate -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2021	- -

Hypercholesterolemia, autosomal dominant, type B

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 23, 2021	- -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

Hypercholesterolemia, familial, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2023

The p.H3570Y variant (also known as c.10708C>T), located in coding exon 26 of the APOB gene, results from a C to T substitution at nucleotide position 10708. The histidine at codon 3570 is replaced by tyrosine, an amino acid with similar properties. This variant (also referred to as H3543Y) has been described in several patients with familial hypercholesterolemia (FH), and a sudden death victim with myocardial infarction (Soufi M et al. Atherosclerosis. 2004;174(1):11-6; Liyanage KE et al. Ann Clin Biochem. 2008;45(Pt 2):170-6; Müllertz KM. Int. J. Cardiol. 2018 07;262:45-50). In a family study, this variant was observed in two relatives with hypercholesterolemia; however, this variant also was seen in a relative with normal LDL-cholesterol, and not reported in a relative with primary hypercholesterolemia and tendon xanthomatosis (Basistová Z et al. Atherosclerosis. 2007;194(2):e185-7). In a recent family study, this variant was reported in an individual with FH, who also had an LDLR mutation detected; her similarly affected daughter had only the LDLR variant (Juhász L et al. Cureus, 2020 Dec;12:e12184). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 08, 2024

Variant summary: APOB c.10708C>T (p.His3570Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250924 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in APOB causing Familial Hypercholesterolemia phenotype (6.3e-05). c.10708C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia, without strong evidence for causality (Soufi_2004, Basistovs_2007, Liyanage_2008, Varret_2008, Toton-Zuranska_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17046772, 18325181, 15135245, 36648309, 18028451). ClinVar contains an entry for this variant (Variation ID: 431988). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Benign

0.22

DANN

Uncertain

0.98

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.19

M_CAP

Benign

0.017

MetaRNN

Benign

0.055

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.38

Sift

Benign

0.42

Sift4G

Benign

0.22

Vest4

0.10

MVP

0.65

MPC

0.041

ClinPred

0.078

GERP RS

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over