rs201736972

chr2-21006160-G-Achr2-21006160-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:2
• Conservation: PhyloP100: -0.109

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]

ACMG classification

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	UniProt
APOB	NM_000384.3	c.10708C>T	p.His3570Tyr	missense_variant	26/29	ENST00000233242.5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152124 Hom.: 0 Cov.: 33

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: 31 AN: 250924 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135574

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.: 0 Cov.: 36 AF XY: 0.000144 AC XY: 105 AN XY: 727174

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: 29 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74300

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.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

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	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) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 04, 2023	BS4, BP4_strong, PS4_moderate -

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:1 Benign:1

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

Hypercholesterolemia, familial, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

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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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.21	T
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	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.38
Sift	Benign	0.42	T
Sift4G	Benign	0.22	T
Vest4		0.10
MVP		0.65
MPC		0.041
ClinPred		0.078	T
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

Other links and lift over

dbSNP: rs201736972; hg19: chr2-21229032;